FN Clarivate Analytics Web of Science VR 1.0 PT J AU Bendall, SC Simonds, EF Qiu, P Amir, EAD Krutzik, PO Finck, R Bruggner, RV Melamed, R Trejo, A Ornatsky, OI Balderas, RS Plevritis, SK Sachs, K Pe'er, D Tanner, SD Nolan, GP AF Bendall, Sean C. Simonds, Erin F. Qiu, Peng Amir, El-ad D. Krutzik, Peter O. Finck, Rachel Bruggner, Robert V. Melamed, Rachel Trejo, Angelica Ornatsky, Olga I. Balderas, Robert S. Plevritis, Sylvia K. Sachs, Karen Pe'er, Dana Tanner, Scott D. Nolan, Garry P. TI Single-Cell Mass Cytometry of Differential Immune and Drug Responses Across a Human Hematopoietic Continuum SO SCIENCE LA English DT Article ID TYROSINE KINASE INHIBITOR; FLOW-CYTOMETRY; SIGNALING NETWORKS; QUANTITATIVE-ANALYSIS; MYELOGENOUS LEUKEMIA; STEM-CELLS; IDENTIFICATION; LYMPHOCYTE; DASATINIB; ACTIVATION AB Flow cytometry is an essential tool for dissecting the functional complexity of hematopoiesis. We used single-cell "mass cytometry" to examine healthy human bone marrow, measuring 34 parameters simultaneously in single cells (binding of 31 antibodies, viability, DNA content, and relative cell size). The signaling behavior of cell subsets spanning a defined hematopoietic hierarchy was monitored with 18 simultaneous markers of functional signaling states perturbed by a set of ex vivo stimuli and inhibitors. The data set allowed for an algorithmically driven assembly of related cell types defined by surface antigen expression, providing a superimposable map of cell signaling responses in combination with drug inhibition. Visualized in this manner, the analysis revealed previously unappreciated instances of both precise signaling responses that were bounded within conventionally defined cell subsets and more continuous phosphorylation responses that crossed cell population boundaries in unexpected manners yet tracked closely with cellular phenotype. Collectively, such single-cell analyses provide system-wide views of immune signaling in healthy human hematopoiesis, against which drug action and disease can be compared for mechanistic studies and pharmacologic intervention. C1 [Bendall, Sean C.; Simonds, Erin F.; Krutzik, Peter O.; Finck, Rachel; Bruggner, Robert V.; Trejo, Angelica; Sachs, Karen; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Qiu, Peng; Plevritis, Sylvia K.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Amir, El-ad D.; Melamed, Rachel; Pe'er, Dana] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Ornatsky, Olga I.; Tanner, Scott D.] Univ Toronto, Toronto, ON M5S 3H6, Canada. [Ornatsky, Olga I.; Tanner, Scott D.] DVS Sci, Markham, ON L3R 6E7, Canada. [Balderas, Robert S.] BD Biosci, San Diego, CA 95131 USA. [Bruggner, Robert V.] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA. C1 [Bendall, Sean C.; Simonds, Erin F.; Krutzik, Peter O.; Finck, Rachel; Bruggner, Robert V.; Trejo, Angelica; Sachs, Karen; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Qiu, Peng; Plevritis, Sylvia K.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Amir, El-ad D.; Melamed, Rachel; Pe'er, Dana] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Ornatsky, Olga I.; Tanner, Scott D.] Univ Toronto, Toronto, ON M5S 3H6, Canada. [Ornatsky, Olga I.; Tanner, Scott D.] DVS Sci, Markham, ON L3R 6E7, Canada. [Balderas, Robert S.] BD Biosci, San Diego, CA 95131 USA. [Bruggner, Robert V.] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA. RP Nolan, GP (reprint author), Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. EM gnolan@stanford.edu EM gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019 OI Pe'er, Dana/0000-0002-9259-8817; Altan-Bonnet, Gregoire/0000-0002-7283-3162; Simonds, Erin/0000-0002-3497-4861; Melamed, Rachel/0000-0003-3089-9806 FU Damon Runyon Cancer Research Foundation [DRG-2017-09]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19 AI057229, P01 CA034233, 272200700038C, 1R01CA130826, U54 CA149145, 5U54 CA143907, RB2-01592, PN2 EY018228, NOI-HV-00242]; European CommissionEuropean Commission Joint Research Centre [HEALTH.2010.1.2-1]; California Institute for Regenerative MedicineCalifornia Institute for Regenerative Medicine [RB2-01592, DR-01477]; Genome Canada via the Ontario Genomics Institute for Cancer Research; Ontario Research Fund [ORF-GL2-01-003]; Burroughs Wellcome FundBurroughs Wellcome Fund; Packard Fellowship for Science and Engineering FX The authors thank W. J. Fantl for critical reading of the. manuscript. S.C.B. is supported by the Damon Runyon Cancer Research Foundation Fellowship (DRG-2017-09). This work was supported by NIH grants, U19 AI057229, P01 CA034233, 272200700038C, 1R01CA130826, U54 CA149145, 5U54 CA143907, RB2-01592, PN2 EY018228, NOI-HV-00242, and HEALTH.2010.1.2-1 (European Commission grant to the Sweden Diatools Consortium), as well as California Institute for Regenerative Medicine (DR-01477, RB2-01592) to G.P.N. G.P.N. is supported by an endowed chair from Rachtford and Carlota A. Harris. S.D.T. was supported by Genome Canada via the Ontario Genomics Institute for Cancer Research and by the Ontario Research Fund ORF-GL2-01-003. D.P. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund and Packard Fellowship for Science and Engineering. Some antibodies were a gift from Becton Dickinson Biosciences. B.B. is a paid employee of Becton Dickinson, and G.P.N. and P.K. are paid consultants for Becton Dickinson Biosciences. G.P.N. is a member of the Board of Directors and a consultant for DVS Sciences. O.O., G.P.N., and S.T. have equity holdings in DVS Biosciences, and S.T. is an employee of DVS Sciences A patent has been applied for on the SPADE algorithm on behalf of Stanford University. Raw data and SPADE trees can be downloaded open access at www.cytobank.org/nolanlab. 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Tadmor, Michelle D. Simonds, Erin F. Levine, Jacob H. Bendall, Sean C. Shenfeld, Daniel K. Krishnaswamy, Smita Nolan, Garry P. Pe'er, Dana TI viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia SO NATURE BIOTECHNOLOGY LA English DT Article ID MINIMAL RESIDUAL DISEASE; FLOW-CYTOMETRY; MASS CYTOMETRY; STEM-CELLS; PROGENITORS; HIERARCHY; NETWORKS; BIOLOGY; GUIDE AB New high-dimensional, single-cell technologies offer unprecedented resolution in the analysis of heterogeneous tissues. However, because these technologies can measure dozens of parameters simultaneously in individual cells, data interpretation can be challenging. Here we present viSNE, a tool that allows one to map high-dimensional cytometry data onto two dimensions, yet conserve the high-dimensional structure of the data. viSNE plots individual cells in a visual similar to a scatter plot, while using all pairwise distances in high dimension to determine each cell's location in the plot. We integrated mass cytometry with viSNE to map healthy and cancerous bone marrow samples. Healthy bone marrow automatically maps into a consistent shape, whereas leukemia samples map into malformed shapes that are distinct from healthy bone marrow and from each other. We also use viSNE and mass cytometry to compare leukemia diagnosis and relapse samples, and to identify a rare leukemia population reminiscent of minimal residual disease. viSNE can be applied to any multi-dimensional single-cell technology. C1 [Amir, El-ad David; Tadmor, Michelle D.; Levine, Jacob H.; Shenfeld, Daniel K.; Krishnaswamy, Smita; Pe'er, Dana] Columbia Univ, Dept Biol Sci, Columbia Initiat Syst Biol, New York, NY 10027 USA. [Davis, Kara L.; Simonds, Erin F.; Bendall, Sean C.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. C1 [Amir, El-ad David; Tadmor, Michelle D.; Levine, Jacob H.; Shenfeld, Daniel K.; Krishnaswamy, Smita; Pe'er, Dana] Columbia Univ, Dept Biol Sci, Columbia Initiat Syst Biol, New York, NY 10027 USA. [Davis, Kara L.; Simonds, Erin F.; Bendall, Sean C.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. RP Pe'er, D (reprint author), Columbia Univ, Dept Biol Sci, Columbia Initiat Syst Biol, New York, NY 10027 USA. EM dpeer@biology.columbia.edu EM dpeer@biology.columbia.edu RI Krishnaswamy, Smita/D-8089-2016; Nolan, Garry/AAE-7903-2019 OI Krishnaswamy, Smita/0000-0001-5823-1985; Simonds, Erin/0000-0002-3497-4861; Pe'er, Dana/0000-0002-9259-8817 FU National Science Foundation CAREER awardNational Science Foundation (NSF) [MCB-1149728]; National Institutes of Health Roadmap InitiativeUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA; NIH Director's New Innovator Award Program [1-DP2-OD002414-01]; National Centers for Biomedical Computing [1U54CA121852-01A1]; Alex's Lemonade Fund Young Investigator Award; St. Baldrick's Foundation Scholar Award; Damon Runyon Cancer Research Foundation Fellowship [DRG-2017-09]; Rachford and Carlota A. Harris Endowed Professorship; European Commission HEALTH [2010.1.2-1]; Bill and Melinda Gates FoundationGates Foundation [GF12141-137101]; [U19 AI057229]; [P01 CA034233]; [HHSN272200700038C]; [1R01CA130826]; [CIRM DR1-01477]; [RB2-01592]; [NCI RFA CA 09-011]; [NHLBIHV-10-05(2)] FX The authors would like to thank N. Friedman, I. Pe'er and O. Litvin for valuable comments. The authors would also like to thank M. Minden (Princess Margaret Hospital), C. Mullighan, J. Downing and I. Radtke (St. Jude Children's Hospital) for generously providing leukemia samples for mass cytometry analysis. This research was supported by the National Science Foundation CAREER award through grant number MCB-1149728, National Institutes of Health Roadmap Initiative, NIH Director's New Innovator Award Program through grant number 1-DP2-OD002414-01 and National Centers for Biomedical Computing Grant 1U54CA121852-01A1. E.D.A. is a Howard Hughes Medical Institute International Student Research Fellow. K.L.D. is supported by Alex's Lemonade Fund Young Investigator Award and St. Baldrick's Foundation Scholar Award. S.C.B. is supported by the Damon Runyon Cancer Research Foundation Fellowship (DRG-2017-09). G.P.N. is supported by the Rachford and Carlota A. Harris Endowed Professorship and grants from U19 AI057229, P01 CA034233, HHSN272200700038C, 1R01CA130826, CIRM DR1-01477 and RB2-01592, NCI RFA CA 09-011, NHLBIHV-10-05(2), European Commission HEALTH. 2010.1.2-1, and the Bill and Melinda Gates Foundation (GF12141-137101). D.P. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund and Packard Fellowship for Science and Engineering. 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Biotechnol. PD JUN PY 2013 VL 31 IS 6 BP 545 EP + DI 10.1038/nbt.2594 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 160IO UT WOS:000320113200027 PM 23685480 OA Green Accepted DA 2020-07-01 ER PT J AU Giesen, C Wang, HAO Schapiro, D Zivanovic, N Jacobs, A Hattendorf, B Schuffler, PJ Grolimund, D Buhmann, JM Brandt, S Varga, Z Wild, PJ Gunther, D Bodenmiller, B AF Giesen, Charlotte Wang, Hao A. O. Schapiro, Denis Zivanovic, Nevena Jacobs, Andrea Hattendorf, Bodo Schueffler, Peter J. Grolimund, Daniel Buhmann, Joachim M. Brandt, Simone Varga, Zsuzsanna Wild, Peter J. Guenther, Detlef Bodenmiller, Bernd TI Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry SO NATURE METHODS LA English DT Article ID SPECTROMETRY; CELLS; HETEROGENEITY; TARGET AB Mass cytometry enables high-dimensional, single-cell analysis of cell type and state. In mass cytometry, rare earth metals are used as reporters on antibodies. Analysis of metal abundances using the mass cytometer allows determination of marker expression in individual cells. Mass cytometry has previously been applied only to cell suspensions. To gain spatial information, we have coupled immunohistochemical and immunocytochemical methods with high-resolution laser ablation to CyTOF mass cytometry. This approach enables the simultaneous imaging of 32 proteins and protein modifications at subcellular resolution; with the availability of additional isotopes, measurement of over 100 markers will be possible. We applied imaging mass cytometry to human breast cancer samples, allowing delineation of cell subpopulations and cell-cell interactions and highlighting tumor heterogeneity. Imaging mass cytometry complements existing imaging approaches. It will enable basic studies of tissue heterogeneity and function and support the transition of medicine toward individualized molecularly targeted diagnosis and therapies. C1 [Giesen, Charlotte; Schapiro, Denis; Zivanovic, Nevena; Jacobs, Andrea; Bodenmiller, Bernd] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. [Wang, Hao A. O.; Hattendorf, Bodo; Guenther, Detlef] Swiss Fed Inst Technol, Dept Chem, Zurich, Switzerland. [Wang, Hao A. O.; Grolimund, Daniel] Paul Scherrer Inst, Swiss Light Source, Villigen, Switzerland. [Schapiro, Denis] Swiss Fed Inst Technol, Life Sci Zurich Grad Sch, Syst Biol PhD Program, Zurich, Switzerland. [Schapiro, Denis; Zivanovic, Nevena] Univ Zurich, Zurich, Switzerland. [Zivanovic, Nevena] Swiss Fed Inst Technol, Life Sci Zurich Grad Sch, Mol Life Sci PhD Program, Zurich, Switzerland. [Schueffler, Peter J.; Buhmann, Joachim M.] Swiss Fed Inst Technol, Dept Comp Sci, Zurich, Switzerland. [Brandt, Simone; Varga, Zsuzsanna; Wild, Peter J.] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland. C1 [Giesen, Charlotte; Schapiro, Denis; Zivanovic, Nevena; Jacobs, Andrea; Bodenmiller, Bernd] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. [Wang, Hao A. O.; Hattendorf, Bodo; Guenther, Detlef] Swiss Fed Inst Technol, Dept Chem, Zurich, Switzerland. [Wang, Hao A. O.; Grolimund, Daniel] Paul Scherrer Inst, Swiss Light Source, Villigen, Switzerland. [Schapiro, Denis] Swiss Fed Inst Technol, Life Sci Zurich Grad Sch, Syst Biol PhD Program, Zurich, Switzerland. [Schapiro, Denis; Zivanovic, Nevena] Univ Zurich, Zurich, Switzerland. [Zivanovic, Nevena] Swiss Fed Inst Technol, Life Sci Zurich Grad Sch, Mol Life Sci PhD Program, Zurich, Switzerland. [Schueffler, Peter J.; Buhmann, Joachim M.] Swiss Fed Inst Technol, Dept Comp Sci, Zurich, Switzerland. [Brandt, Simone; Varga, Zsuzsanna; Wild, Peter J.] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland. RP Bodenmiller, B (reprint author), Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. EM guenther@inorg.chem.ethz.ch; bernd.bodenmiller@imls.uzh.ch EM guenther@inorg.chem.ethz.ch; bernd.bodenmiller@imls.uzh.ch RI Grolimund, Daniel/O-3127-2017; MS-Powder+MS-Surfdiff+Micro-XAS+Super-XAS, SLS/M-1551-2019; Schuffler, Peter/C-1821-2018 OI Grolimund, Daniel/0000-0001-9721-7940; Schuffler, Peter/0000-0002-1353-8921; Schapiro, Denis/0000-0002-9391-5722; Hattendorf, Bodo/0000-0001-9991-2410 FU Society in Science; The Branco Weiss Fellowship; Swiss National Science Foundation (SNSF)Swiss National Science Foundation (SNSF) [200021-119779, 31003A-143877]; ETH Zurich Pioneer Fellowship; SystemsX PhosphoNet-PPM; Baugarten Foundation; EU VIGOR++ project [270379]; SNSF R'Equip [316030-139220]; SNSF Assistant Professorship [PP00P3-144874]; Swiss Cancer League; European Research Council (ERC) under the European Union's Seventh Framework ProgrammeEuropean Research Council (ERC) [336921] FX We thank M. Storz for preparing the histological slides and the TMA sections; S. Dettwiler, A. Bohnert, A. Fitsche; the entire Trace Element and Micro Analysis group at ETH Zurich for their experimental support and discussions; N. Daga and C. von Mering for their feedback on data analysis; the ETHZ LAC workshop for their support in design and construction of the laser ablation chamber; and the Lehner and Luschnig groups for giving us access to their immunofluorescence microscopes. This work was supported by a Society in Science, The Branco Weiss Fellowship, administered by the ETH Zurich (C.G.); the Swiss National Science Foundation (SNSF) project grants 200021-119779 (H.A.O.W.), 200021- 119779 (D.Gunther), 31003A-143877 (D.Gunther) and 31003A- 143877(B.B.); an ETH Zurich Pioneer Fellowship (H.A.O.W.); the SystemsX PhosphoNet-PPM grant (P.J.W. and B.B.); a Baugarten Foundation grant (SGGP) (P.J.W.); a EU VIGOR++ project FP7/2007-2013, # 270379 (P.J.S. and J. M. B.); an SNSF R'Equip grant 316030-139220 (B. B.); an SNSF Assistant Professorship grant PP00P3- 144874 (B.B.); a Swiss Cancer League grant (B.B.); and funding from the European Research Council (ERC) under the European Union's Seventh Framework Programme (FP7/2007-2013)/ ERC Grant Agreement no. 336921 (B.B.). CR Bandura DR, 2009, ANAL CHEM, V81, P6813, DOI 10.1021/ac901049w Becker JS, 2010, ANAL CHEM, V82, P9528, DOI 10.1021/ac102256q Bendall SC, 2011, SCIENCE, V332, P687, DOI 10.1126/science.1198704 Blurry R. 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Methods PD APR PY 2014 VL 11 IS 4 BP 417 EP + DI 10.1038/NMETH.2869 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AE1SL UT WOS:000333749900024 PM 24584193 DA 2020-07-01 ER PT J AU Qiu, P Simonds, EF Bendall, SC Gibbs, KD Bruggner, RV Linderman, MD Sachs, K Nolan, GP Plevritis, SK AF Qiu, Peng Simonds, Erin F. Bendall, Sean C. Gibbs, Kenneth D., Jr. Bruggner, Robert V. Linderman, Michael D. Sachs, Karen Nolan, Garry P. Plevritis, Sylvia K. TI Extracting a cellular hierarchy from high-dimensional cytometry data with SPADE SO NATURE BIOTECHNOLOGY LA English DT Article ID FLOW-CYTOMETRY; MASS CYTOMETRY; STEM-CELL; IDENTIFICATION; IMMUNE AB The ability to analyze multiple single-cell parameters is critical for understanding cellular heterogeneity. Despite recent advances in measurement technology, methods for analyzing high-dimensional single-cell data are often subjective, labor intensive and require prior knowledge of the biological system. To objectively uncover cellular heterogeneity from single-cell measurements, we present a versatile computational approach, spanning-tree progression analysis of density-normalized events (SPADE). We applied SPADE to flow cytometry data of mouse bone marrow and to mass cytometry data of human bone marrow. In both cases, SPADE organized cells in a hierarchy of related phenotypes that partially recapitulated well-described patterns of hematopoiesis. We demonstrate that SPADE is robust to measurement noise and to the choice of cellular markers. SPADE facilitates the analysis of cellular heterogeneity, the identification of cell types and comparison of functional markers in response to perturbations. C1 [Qiu, Peng; Plevritis, Sylvia K.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Qiu, Peng] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Simonds, Erin F.; Bendall, Sean C.; Gibbs, Kenneth D., Jr.; Bruggner, Robert V.; Sachs, Karen; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Linderman, Michael D.] Stanford Univ, Comp Syst Lab, Stanford, CA 94305 USA. C1 [Qiu, Peng; Plevritis, Sylvia K.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Qiu, Peng] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Simonds, Erin F.; Bendall, Sean C.; Gibbs, Kenneth D., Jr.; Bruggner, Robert V.; Sachs, Karen; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Linderman, Michael D.] Stanford Univ, Comp Syst Lab, Stanford, CA 94305 USA. RP Qiu, P (reprint author), Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. EM pqiu@mdanderson.org EM pqiu@mdanderson.org RI Nolan, Garry/AAE-7903-2019 OI Simonds, Erin/0000-0002-3497-4861; Gibbs, Kenneth/0000-0002-3532-5396 FU National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U56CA112973, U54CA149145]; A Damon Runyon Cancer Research Foundation; National Science FoundationNational Science Foundation (NSF); Stanford DARE; US National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19 AI057229, P01 CA034233, HHSN272200700038C, 1R01CA130826, 5U54 CA143907, RB2-01592, PN2EY018228, N01-HV-00242]; European CommissionEuropean Commission Joint Research Centre [HEALTH.2010.1.2-1]; California Institute for Regenerative MedicineCalifornia Institute for Regenerative Medicine [DR1-01477] FX The authors gratefully acknowledge funding from National Cancer Institute Integrative Cancer Biology Program (ICBP), grants U56CA112973 and U54CA149145 to S.K.P. A Damon Runyon Cancer Research Foundation Fellowship supports S.C.B. National Science Foundation Graduate Research Fellowship and Stanford DARE Fellowship support K. D. G. This work is also supported by US National Institutes of Health grants U19 AI057229, P01 CA034233, HHSN272200700038C, 1R01CA130826, 5U54 CA143907, RB2-01592, PN2EY018228, N01-HV-00242, HEALTH.2010.1.2-1 (European Commission), as well as the California Institute for Regenerative Medicine (DR1-01477) to G.P.N. 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PD MAR PY 2012 VL 12 IS 3 BP 191 EP 200 DI 10.1038/nri3158 PG 10 WC Immunology SC Immunology GA 899CJ UT WOS:000300790600013 PM 22343568 OA Green Accepted DA 2020-07-01 ER PT J AU Ransohoff, RM AF Ransohoff, Richard M. TI A polarizing question: do M1 and M2 microglia exist? SO NATURE NEUROSCIENCE LA English DT Article ID PRONEUROGENIC PHENOTYPE; MACROPHAGE ACTIVATION; ANALYSIS REVEALS; ADULT MICROGLIA; NEURONAL DEATH; MYELOID CELLS; MOUSE; EXPRESSION; FATE; TRANSCRIPTOME AB Microglial research has entered a fertile, dynamic phase characterized by novel technologies including two-photon imaging, whole-genome transcriptomic and epigenomic analysis with complementary bioinformatics, unbiased proteomics, cytometry by time of flight (CyTOF; Fluidigm) cytometry, and complex high-content experimental models including slice culture and zebrafish. Against this vivid background of newly emerging data, investigators will encounter in the microglial research literature a body of published work using the terminology of macrophage polarization, most commonly into the M1 and M2 phenotypes. It is the assertion of this opinion piece that microglial polarization has not been established by research findings. Rather, the adoption of this schema was undertaken in an attempt to simplify data interpretation at a time when the ontogeny and functional significance of microglia had not yet been characterized. Now, terminology suggesting established meaningful pathways of microglial polarization hinders rather than aids research progress and should be discarded. C1 [Ransohoff, Richard M.] Biogen Inc, Neuroimmunol, 14 Cambridge Ctr, Cambridge, MA 02142 USA. C1 [Ransohoff, Richard M.] Biogen Inc, Neuroimmunol, 14 Cambridge Ctr, Cambridge, MA 02142 USA. RP Ransohoff, RM (reprint author), Biogen Inc, Neuroimmunol, 14 Cambridge Ctr, Cambridge, MA 02142 USA. 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Neurosci. PD AUG PY 2016 VL 19 IS 8 BP 987 EP 991 DI 10.1038/nn.4338 PG 5 WC Neurosciences SC Neurosciences & Neurology GA DS4TB UT WOS:000380773200004 PM 27459405 DA 2020-07-01 ER PT J AU Levine, JH Simonds, EF Bendall, SC Davis, KL Amir, EAD Tadmor, MD Litvin, O Fienberg, HG Jager, A Zunder, ER Finck, R Gedman, AL Radtke, I Downing, JR Pe'er, D Nolan, GP AF Levine, Jacob H. Simonds, Erin F. Bendall, Sean C. Davis, Kara L. Amir, El-ad D. Tadmor, Michelle D. Litvin, Oren Fienberg, Harris G. Jager, Astraea Zunder, Eli R. Finck, Rachel Gedman, Amanda L. Radtke, Ina Downing, James R. Pe'er, Dana Nolan, Garry P. TI Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis SO CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MASS CYTOMETRY; HETEROGENEITY; CANCER; DECONVOLUTION AB Acute myeloid leukemia (AML) manifests as phenotypically and functionally diverse cells, often within the same patient. Intratumor phenotypic and functional heterogeneity have been linked primarily by physical sorting experiments, which assume that functionally distinct subpopulations can be prospectively isolated by surface phenotypes. This assumption has proven problematic, and we therefore developed a data-driven approach. Using mass cytometry, we profiled surface and intracellular signaling proteins simultaneously in millions of healthy and leukemic cells. We developed PhenoGraph, which algorithmically defines phenotypes in high-dimensional single-cell data. PhenoGraph revealed that the surface phenotypes of leukemic blasts do not necessarily reflect their intracellular state. Using hematopoietic progenitors, we defined a signaling-based measure of cellular phenotype, which led to isolation of a gene expression signature that was predictive of survival in independent cohorts. This study presents new methods for large-scale analysis of single-cell heterogeneity and demonstrates their utility, yielding insights into AML pathophysiology. C1 [Levine, Jacob H.; Amir, El-ad D.; Tadmor, Michelle D.; Litvin, Oren; Pe'er, Dana] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Levine, Jacob H.; Amir, El-ad D.; Tadmor, Michelle D.; Litvin, Oren; Pe'er, Dana] Columbia Univ, Dept Syst Biol, New York, NY 10027 USA. [Simonds, Erin F.; Davis, Kara L.; Fienberg, Harris G.; Jager, Astraea; Zunder, Eli R.; Finck, Rachel; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Bendall, Sean C.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Gedman, Amanda L.; Radtke, Ina; Downing, James R.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. C1 [Levine, Jacob H.; Amir, El-ad D.; Tadmor, Michelle D.; Litvin, Oren; Pe'er, Dana] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Levine, Jacob H.; Amir, El-ad D.; Tadmor, Michelle D.; Litvin, Oren; Pe'er, Dana] Columbia Univ, Dept Syst Biol, New York, NY 10027 USA. [Simonds, Erin F.; Davis, Kara L.; Fienberg, Harris G.; Jager, Astraea; Zunder, Eli R.; Finck, Rachel; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Bendall, Sean C.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Gedman, Amanda L.; Radtke, Ina; Downing, James R.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. RP Pe'er, D (reprint author), Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. EM dpeer@biology.columbia.edu; gnolan@stanford.edu EM dpeer@biology.columbia.edu; gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019; Downing, James R./N-8102-2018 OI Pe'er, Dana/0000-0002-9259-8817; Simonds, Erin/0000-0002-3497-4861 FU DRCRF Fellowships [DRG 2190-14, DRG-2017-09]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R00-GM104148, DP1-HD084071, DP2-OD002414, R01-CA164729 U54-CA121852, 1R01CA130826, 5U54CA143907, HHSN272200700038C, N01-HV-00242, P01 CA034233, U19 AI057229, U54CA149145]; Stand Up To Cancer Phillip A. Sharp Award [SU2C-AACR-PS04]; CIRMCalifornia Institute for Regenerative Medicine [DR1-01477, RB2-01592]; ECEuropean Commission Joint Research CentreEuropean Community (EC) [HEALTH.2010.1.2-1]; US FDAUnited States Department of Health & Human Services [HHSF223201210194C]; US DODUnited States Department of Defense [W81XWH-12-1-0591]; Entertainment Industry Foundation; Rachford and Carlota Harris Endowed Professorship; Packard Fellowship for Science and Engineering FX We thank G. Behbehani, W. Fantl, B.J. Chen, and L. Zelnik for helpful discussion. E.F.S. and S.C.B. are supported by DRCRF Fellowships (DRG 2190-14 & DRG-2017-09) and NIH 1R00-GM104148 to S.C.B. Grants from NIH (DP1-HD084071, DP2-OD002414, R01-CA164729 U54-CA121852), Stand Up To Cancer Phillip A. Sharp Award SU2C-AACR-PS04 and Packard Fellowship for Science and Engineering supported D.P. Grants from NIH (1R01CA130826, 5U54CA143907, HHSN272200700038C, N01-HV-00242, P01 CA034233, U19 AI057229 and U54CA149145), CIRM (DR1-01477 and RB2-01592), EC (HEALTH.2010.1.2-1), US FDA (HHSF223201210194C), US DOD (W81XWH-12-1-0591), the Entertainment Industry Foundation, and the Rachford and Carlota Harris Endowed Professorship supported G.P.N. G.P.N., S.C.B, H.G.F., and E.F.S. have a personal financial interest in the company Fluidigm, the manufacturer of the mass cytometer used in this manuscript. 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Davis, Kara L. Amir, El-ad David Tadmor, Michelle D. Simonds, Erin F. Chen, Tiffany J. Shenfeld, Daniel K. Nolan, Garry P. Pe'er, Dana TI Single-Cell Trajectory Detection Uncovers Progression and Regulatory Coordination in Human B Cell Development SO CELL LA English DT Article ID MASS CYTOMETRY; IMMUNOGLOBULIN; LYMPHOCYTES; MURINE; STAT5 AB Tissue regeneration is an orchestrated progression of cells from an immature state to amature one, conventionally represented as distinctive cell subsets. A continuum of transitional cell states exists between these discrete stages. We combine the depth of single-cell mass cytometry and an algorithm developed to leverage this continuumby aligning single cells of a given lineage onto a unified trajectory that accurately predicts the developmental path de novo. Applied to human B cell lymphopoiesis, the algorithm (termed Wanderlust) constructed trajectories spanning from hematopoietic stem cells through to naive B cells. This trajectory revealed nascent fractions of B cell progenitors and aligned them with developmentally cued regulatory signaling including IL-7/STAT5 and cellular events such as immunoglobulin rearrangement, highlighting checkpoints across which regulatory signals are rewired paralleling changes in cellular state. This study provides a comprehensive analysis of human B lymphopoiesis, laying a foundation to apply this approach to other tissues and "corrupted'' developmental processes including cancer. C1 [Bendall, Sean C.; Davis, Kara L.; Simonds, Erin F.; Chen, Tiffany J.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Bendall, Sean C.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Davis, Kara L.] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [Amir, El-ad David; Tadmor, Michelle D.; Shenfeld, Daniel K.; Pe'er, Dana] Columbia Univ, Dept Biol Sci, Dept Syst Biol, New York, NY 10027 USA. [Chen, Tiffany J.] Stanford Univ, Program Biomed Informat, Stanford, CA 94305 USA. [Chen, Tiffany J.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. C1 [Bendall, Sean C.; Davis, Kara L.; Simonds, Erin F.; Chen, Tiffany J.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Bendall, Sean C.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Davis, Kara L.] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [Amir, El-ad David; Tadmor, Michelle D.; Shenfeld, Daniel K.; Pe'er, Dana] Columbia Univ, Dept Biol Sci, Dept Syst Biol, New York, NY 10027 USA. [Chen, Tiffany J.] Stanford Univ, Program Biomed Informat, Stanford, CA 94305 USA. [Chen, Tiffany J.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. RP Nolan, GP (reprint author), Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. EM gnolan@stanford.edu; dpeer@biology.columbia.edu EM gnolan@stanford.edu; dpeer@biology.columbia.edu RI Nolan, Garry/AAE-7903-2019 OI Pe'er, Dana/0000-0002-9259-8817; Simonds, Erin/0000-0002-3497-4861 FU St. Baldrick's Foundation Scholar Award; Alex's Lemonade Stand Young Investigator Award; Lucile Packard Foundation for Children's Health; NIH-NCATS-CTSAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1 TR001085]; Child Health Research Institute of Stanford University; Damon Runyon Cancer Research Foundation Fellowship [DRG-2017-09]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [K99GM104148-01, S10 SIG S10RR027582-01, 152175.5041015.0412, DP2-OD002414-01, U54CA121852-01A1]; National Defense Science & Engineering Graduate Fellowship Program; Stanford University Graduate FellowshipStanford University; Google Anita Borg Memorial Scholarship; William Lawrence and Blanche Hughes Foundation; Entertainment Industry Foundation; Northrup-Grumman Corp; Alliance for Lupus Research; Lymphoma Research Foundation; Bill and Melinda Gates FoundationGates Foundation; NSFNational Science Foundation (NSF) [MCB-1149728]; Packard Fellowship for Science and Engineering; [0158 G KB065]; [1R01CA130826]; [5U54CA143907NIH]; [CIRM: DR1-01477]; [HEALTH.2010.1.2-1]; [HHSF223201210194C - FDA: BAA-12-00118]; [HHSN272200700038C]; [N01-HV-00242]; [NIH 41000411217]; [NIH 5-24927]; [P01 CA034233-22A1]; [PN2EY018228]; [RB2-01592]; [U19 AI057229]; [U54CA149145]; [W81XWH-12-1-0591] FX We would like to thank Omer Angel, Antonio de-la-Hera, Astraea Jager, Ulf Klein, Smita Krishnaswamy, Jacob Levine, Eva Sanz, Peter Sims, and Angelica Trejo for their intellectual and technical contributions. K.L.D. is supported by a St. Baldrick's Foundation Scholar Award, Alex's Lemonade Stand Young Investigator Award and the Lucile Packard Foundation for Children's Health, Stanford NIH-NCATS-CTSA UL1 TR001085 and Child Health Research Institute of Stanford University. S.C.B. is supported by the Damon Runyon Cancer Research Foundation Fellowship (DRG-2017-09) and the NIH K99GM104148-01. E.D.A. is a Howard Hughes Medical Institute International Student Research Fellow. T.J.C. is supported by National Defense Science & Engineering Graduate Fellowship Program, Stanford University Graduate Fellowship, and the Google Anita Borg Memorial Scholarship. This work was supported by 0158 G KB065; 1R01CA130826; 5U54CA143907NIH; CIRM: DR1-01477; HEALTH.2010.1.2-1; HHSF223201210194C - FDA: BAA-12-00118; HHSN272200700038C; N01-HV-00242; NIH 41000411217; NIH 5-24927; P01 CA034233-22A1; PN2EY018228; RB2-01592; U19 AI057229; U54CA149145; W81XWH-12-1-0591 OCRP-TIA NWC; NIH S10 SIG S10RR027582-01, William Lawrence and Blanche Hughes Foundation, Entertainment Industry Foundation, Northrup-Grumman Corp, Alliance for Lupus Research, Lymphoma Research Foundation, Bill and Melinda Gates Foundation, NIH 152175.5041015.0412 and the Rachford and Carlota A. Harris Endowment to G.P.N. This work was supported by NSF MCB-1149728, NIH DP2-OD002414-01, NIH U54CA121852-01A1 to D.P. D.P. holds a Packard Fellowship for Science and Engineering. G.P.N. has personal financial interest in and S.C.B. is a paid consultant for the company DVS Sciences, the manufacturers that produced some of the reagents and instrumentation used in this manuscript. 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Sigal, Natalia Bendall, Sean C. Nolan, Garry P. Davis, Mark M. TI Cytometry by Time-of-Flight Shows Combinatorial Cytokine Expression and Virus-Specific Cell Niches within a Continuum of CD8(+) T Cell Phenotypes SO IMMUNITY LA English DT Article ID CLASS-I LIGANDS; EFFECTOR FUNCTIONS; PEPTIDE COMPLEXES; MHC TETRAMERS; MEMORY; ANTIGEN; LYMPHOCYTES; SUBSETS; RESPONSES; IMMUNE AB Cytotoxic CD8(+) T lymphocytes directly kill infected or aberrant cells and secrete proinflammatory cytokines. By using metal-labeled probes and mass spectrometric analysis (cytometry by time-of-flight, or CyTOF) of human CD8(+) T cells, we analyzed the expression of many more proteins than previously possible with fluorescent labels, including surface markers, cytokines, and antigen specificity with modified peptide-MHC tetramers. With 3-dimensional principal component analysis (3D-PCA) to display phenotypic diversity, we observed a relatively uniform pattern of variation in all subjects tested, highlighting the interrelatedness of previously described subsets and the continuous nature of CD8(+) T cell differentiation. These data also showed much greater complexity in the CD8(+) T cell compartment than previously appreciated, including a nearly combinatorial pattern of cytokine expression, with distinct niches occupied by virus-specific cells. This large degree of functional diversity even between cells with the same specificity gives CD8(+) T cells a remarkable degree of flexibility in responding to pathogens. C1 [Newell, Evan W.; Bendall, Sean C.; Nolan, Garry P.; Davis, Mark M.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Sigal, Natalia; Nolan, Garry P.; Davis, Mark M.] Stanford Univ, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. [Davis, Mark M.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. C1 [Newell, Evan W.; Bendall, Sean C.; Nolan, Garry P.; Davis, Mark M.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Sigal, Natalia; Nolan, Garry P.; Davis, Mark M.] Stanford Univ, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. [Davis, Mark M.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. RP Davis, MM (reprint author), Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. EM mmdavis@stanford.edu EM mmdavis@stanford.edu RI Newell, Evan W/F-9711-2012; Newell, Evan/AAE-9470-2020; Nolan, Garry/AAE-7903-2019 OI Newell, Evan W/0000-0002-2889-243X; Newell, Evan/0000-0002-2889-243X; FU NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19-AI057229, U19-AI090019]; Bill and Melinda Gates FoundationGates Foundation; Howard Hughes Medical InstituteHoward Hughes Medical Institute; American Cancer SocietyAmerican Cancer Society; Damon Runyon Postdoctoral Fellowship [DRG-2017-09] FX The authors would like to thank D. Parks and W. Moore for helpful discussions and help with FlowJo and FCS files, P. Lund for helpful discussions and a T cell stimulation protocol, M. Leipold for help with CyTOF machine maintenance, E. Zunder, B. Bodenmiller, and E. Simonds for general help with CyTOF usage, and A. Han, B. Kidd, W. O'Gorman, O. Goldberger, and Y.-h. Chien for helpful discussions. This work was supported by NIH grants U19-AI057229 and U19-AI090019, Bill and Melinda Gates Foundation Grand Challenges Exploration phase land II grants, and The Howard Hughes Medical Institute. E.W.N. is supported by The American Cancer Society's Steven Stanley and Edward Albert Bielfelt Post-Doctoral Fellowship. S.C.B. is supported by a Damon Runyon Postdoctoral Fellowship (DRG-2017-09). G.P.N. is supported by an endowed chair from Rachtford and Carlota A. Harris. G.P.N. is a paid consultant for Becton Dickinson Biosciences, a member of the Board of Directors and consultant for DVS Sciences, and has equity holdings in DVS Biosciences. 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Nolan, Garry P. Roederer, Mario Chattopadhyay, Pratip K. TI A deep profiler's guide to cytometry SO TRENDS IN IMMUNOLOGY LA English DT Review DE fluorescence; inductively coupled plasma mass spectrometry; single cell analysis; immunophenotyping; data analysis ID ELEMENT-TAGGED IMMUNOASSAY; FLOW-CYTOMETRY; MASS CYTOMETRY; CYTOKINE EXPRESSION; MULTIPLEX BIOASSAY; T-CELLS; POLYMER; IDENTIFICATION; PHYCOERYTHRIN; LYMPHOCYTES AB In recent years, advances in technology have provided us with tools to quantify the expression of multiple genes in individual cells. The ability to measure simultaneously multiple genes in the same cell is necessary to resolve the great diversity of cell subsets, as well as to define their function in the host. Fluorescence-based flow cytometry is the benchmark for this; with it, we can quantify 18 proteins per cell, at >10 000 cells/s. Mass cytometry is a new technology that promises to extend these capabilities significantly. Immunophenotyping by mass spectrometry provides the ability to measure >36 proteins at a rate of 1000 cells/s. We review these cytometric technologies, capable of high-content, high-throughput single-cell assays. C1 [Roederer, Mario; Chattopadhyay, Pratip K.] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Bendall, Sean C.; Nolan, Garry P.] Stanford Univ, Baxter Lab Stem Cell Biol, Dept Microbiol & Immunol, Stanford, CA 94305 USA. C1 [Roederer, Mario; Chattopadhyay, Pratip K.] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Bendall, Sean C.; Nolan, Garry P.] Stanford Univ, Baxter Lab Stem Cell Biol, Dept Microbiol & Immunol, Stanford, CA 94305 USA. RP Roederer, M (reprint author), NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM Roederer@nih.gov EM Roederer@nih.gov RI Nolan, Garry/AAE-7903-2019 OI Chattopadhyay, Pratip/0000-0002-5457-9666 FU Intramural Research Program of the NIAID, NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID); Collaboration for AIDS Vaccine Discovery (CAVD), from the Bill and Melinda Gates Foundation [OPP1032325]; Damon Runyon Cancer Research Foundation Fellowship [DRG-2017-09]; Rachford and Carlota A. Harris Endowed Professorship; European CommissionEuropean Commission Joint Research Centre [HEALTH.2010.1.2-1]; Bill and Melinda Gates FoundationGates Foundation [GF12141-137101]; [U19 AI057229]; [P01 CA034233]; [HHSN272200700038C]; [1R01CA130826]; [CIRM DR1-01477]; [RB2-01592]; [NCI RFA CA 09-011]; [NHLBI-HV-10-05(2)] FX M.R. and P.K.C. are supported by the Intramural Research Program of the NIAID, NIH, and by the Collaboration for AIDS Vaccine Discovery (CAVD), Grant #OPP1032325, from the Bill and Melinda Gates Foundation. S.C.B. is supported by the Damon Runyon Cancer Research Foundation Fellowship (DRG-2017-09). G.P.N. is supported by the Rachford and Carlota A. Harris Endowed Professorship and grants from U19 AI057229, P01 CA034233, HHSN272200700038C, 1R01CA130826, CIRM DR1-01477 and RB2-01592, NCI RFA CA 09-011, NHLBI-HV-10-05(2), European Commission HEALTH.2010.1.2-1, and the Bill and Melinda Gates Foundation (GF12141-137101). 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PD JUL PY 2012 VL 33 IS 7 BP 323 EP 332 DI 10.1016/j.it.2012.02.010 PG 10 WC Immunology SC Immunology GA 977EP UT WOS:000306639500001 PM 22476049 OA Green Accepted DA 2020-07-01 ER PT J AU Spitzer, MH Nolan, GP AF Spitzer, Matthew H. Nolan, Garry P. TI Mass Cytometry: Single Cells, Many Features SO CELL LA English DT Article ID FLOW-CYTOMETRY; IMMUNE-SYSTEM; IDENTIFICATION; EXPRESSION; PROGRESSION; DIVERSITY; RESPONSES AB Technology development in biological research often aims to either increase the number of cellular features that can be surveyed simultaneously or enhance the resolution at which such observations are possible. For decades, flow cytometry has balanced these goals to fill a critical need by enabling the measurement of multiple features in single cells, commonly to examine complex or hierarchical cellular systems. Recently, a format for flow cytometry has been developed that leverages the precision of mass spectrometry. This fusion of the two technologies, termed mass cytometry, provides measurement of over 40 simultaneous cellular parameters at single-cell resolution, significantly augmenting the ability of cytometry to evaluate complex cellular systems and processes. In this Primer, we review the current state of mass cytometry, providing an overview of the instrumentation, its present capabilities, and methods of data analysis, as well as thoughts on future developments and applications. C1 [Spitzer, Matthew H.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Spitzer, Matthew H.; Nolan, Garry P.] Stanford Univ, Program Immunol, Stanford, CA 94305 USA. [Spitzer, Matthew H.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Spitzer, Matthew H.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. C1 [Spitzer, Matthew H.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Spitzer, Matthew H.; Nolan, Garry P.] Stanford Univ, Program Immunol, Stanford, CA 94305 USA. [Spitzer, Matthew H.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Spitzer, Matthew H.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. RP Spitzer, MH; Nolan, GP (reprint author), Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA.; Spitzer, MH; Nolan, GP (reprint author), Stanford Univ, Program Immunol, Stanford, CA 94305 USA.; Spitzer, MH (reprint author), Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.; Spitzer, MH (reprint author), Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. EM matthew.spitzer@ucsf.edu; gnolan@stanford.edu EM matthew.spitzer@ucsf.edu; gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019 OI Spitzer, Matthew/0000-0002-5291-3819 FU company Fluidigm FX G.P.N. has a personal financial interest in the company Fluidigm, the manufacturer of the mass cytometer referenced in this study. 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Finck, Rachel Chen, Tiffany J. Savig, Erica S. Bruggner, Robert V. Simonds, Erin F. Bendall, Sean C. Sachs, Karen Krutzik, Peter O. Nolan, Garry P. TI Multiplexed mass cytometry profiling of cellular states perturbed by small-molecule regulators SO NATURE BIOTECHNOLOGY LA English DT Article ID KINASE INHIBITOR SELECTIVITY; POLYCHROMATIC FLOW-CYTOMETRY; FUNCTIONAL GENOMICS; DRUG DISCOVERY; IMMUNE-SYSTEM; CANCER; CELLS; PROTEOMICS; RESPONSES; POPULATIONS AB Mass cytometry facilitates high-dimensional, quantitative analysis of the effects of bioactive molecules on human samples at single-cell resolution, but instruments process only one sample at a time. Here we describe mass-tag cellular barcoding (MCB), which increases mass cytometry throughput by using n metal ion tags to multiplex up to 2(n) samples. We used seven tags to multiplex an entire 96-well plate, and applied MCB to characterize human peripheral blood mononuclear cell (PBMC) signaling dynamics and cell-to-cell communication, signaling variability between PBMCs from eight human donors, and the effects of 27 inhibitors on this system. For each inhibitor, we measured 14 phosphorylation sites in 14 PBMC types at 96 conditions, resulting in 18,816 quantified phosphorylation levels from each multiplexed sample. This high-dimensional, systems-level inquiry allowed analysis across cell-type and signaling space, reclassified inhibitors and revealed off-target effects. High-content, high-throughput screening with MCB should be useful for drug discovery, preclinical testing and mechanistic investigation of human disease. C1 [Bodenmiller, Bernd; Zunder, Eli R.; Finck, Rachel; Chen, Tiffany J.; Savig, Erica S.; Bruggner, Robert V.; Simonds, Erin F.; Bendall, Sean C.; Sachs, Karen; Krutzik, Peter O.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Chen, Tiffany J.; Bruggner, Robert V.] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA. [Chen, Tiffany J.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Savig, Erica S.] Stanford Univ, Canc Biol Program, Stanford, CA 94305 USA. C1 [Bodenmiller, Bernd; Zunder, Eli R.; Finck, Rachel; Chen, Tiffany J.; Savig, Erica S.; Bruggner, Robert V.; Simonds, Erin F.; Bendall, Sean C.; Sachs, Karen; Krutzik, Peter O.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Chen, Tiffany J.; Bruggner, Robert V.] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA. [Chen, Tiffany J.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Savig, Erica S.] Stanford Univ, Canc Biol Program, Stanford, CA 94305 USA. RP Nolan, GP (reprint author), Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. EM gnolan@stanford.edu EM gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019 OI Simonds, Erin/0000-0002-3497-4861 FU Swiss National Science Foundation (SNF)Swiss National Science Foundation (SNSF); European Molecular Biology Organization (EMBO)European Molecular Biology Organization (EMBO); Marie Curie IOFEuropean Union (EU); National Institute of General Medical SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [F32GM093508]; Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program; Stanford Graduate Fellowship in Science and Engineering; Damon Runyon Cancer Research Foundation Fellowship [DRG-2017-09]; Rachford and Carlota A. Harris Endowed Professorship; European CommissionEuropean Commission Joint Research Centre [HEALTH.2010.1.2-1]; Bill and Melinda Gates FoundationGates Foundation [GF12141-137101]; [U19 AI057229]; [P01 CA034233]; [HHSN272200700038C]; [1R01CA130826]; [CIRM DR1-01477]; [RB2-01592]; [NCI RFA CA 09-011]; [NHLBI-HV-10-05(2)] FX We would like to thank A. Trejo, M. Clutter, K. Gibbs and G. Behbahani for their experimental support and discussions, and D. Pe'er and El-ad D. Amir for their feedback on data analysis. B. B. was supported by fellowships of the Swiss National Science Foundation (SNF), the European Molecular Biology Organization (EMBO), and the Marie Curie IOF. E.R.Z. is supported by a fellowship from National Institute of General Medical Sciences (F32GM093508). T.J.C. is supported by the Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program, and the Stanford Graduate Fellowship in Science and Engineering. S. C. B. is supported by the Damon Runyon Cancer Research Foundation Fellowship (DRG-2017-09). G.P.N. is supported by the Rachford and Carlota A. Harris Endowed Professorship and grants from U19 AI057229, P01 CA034233, HHSN272200700038C, 1R01CA130826, CIRM DR1-01477 and RB2-01592, NCI RFA CA 09-011, NHLBI-HV-10-05(2), European Commission HEALTH.2010.1.2-1, and the Bill and Melinda Gates Foundation (GF12141-137101). 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Biotechnol. PD SEP PY 2012 VL 30 IS 9 BP 858 EP U89 DI 10.1038/nbt.2317 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 004UD UT WOS:000308705700020 PM 22902532 OA Green Accepted DA 2020-07-01 ER PT J AU Wei, SC Levine, JH Cogdill, AP Zhao, Y Anang, NAAS Andrews, MC Sharma, P Wang, J Wargo, JA Pe'er, D Allison, JP AF Wei, Spencer C. Levine, Jacob H. Cogdill, Alexandria P. Zhao, Yang Anang, Nana-Ama A. S. Andrews, Miles C. Sharma, Padmanee Wang, Jing Wargo, Jennifer A. Pe'er, Dana Allison, James P. TI Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade SO CELL LA English DT Article ID REGULATORY T-CELLS; MASS CYTOMETRY; CANCER-IMMUNOTHERAPY; CTLA-4 BLOCKADE; COMBINATION IMMUNOTHERAPY; METASTATIC MELANOMA; PROGRAMMED DEATH-1; SOLID TUMORS; THERAPY; IMMUNE AB Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor-infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhaustedlike CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune responses are driven by distinct cellular mechanisms. C1 [Wei, Spencer C.; Cogdill, Alexandria P.; Anang, Nana-Ama A. S.; Allison, James P.] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. [Levine, Jacob H.; Pe'er, Dana] Sloan Kettering Inst, Computat & Syst Biol Program, New York, NY 10065 USA. [Cogdill, Alexandria P.; Andrews, Miles C.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Zhao, Yang; Wang, Jing] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Sharma, Padmanee] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA. [Sharma, Padmanee; Wargo, Jennifer A.; Allison, James P.] Univ Texas MD Anderson Canc Ctr, Parker Inst Canc Immunotherapy, Houston, TX 77030 USA. [Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. C1 [Wei, Spencer C.; Cogdill, Alexandria P.; Anang, Nana-Ama A. S.; Allison, James P.] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. [Levine, Jacob H.; Pe'er, Dana] Sloan Kettering Inst, Computat & Syst Biol Program, New York, NY 10065 USA. [Cogdill, Alexandria P.; Andrews, Miles C.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Zhao, Yang; Wang, Jing] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Sharma, Padmanee] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA. [Sharma, Padmanee; Wargo, Jennifer A.; Allison, James P.] Univ Texas MD Anderson Canc Ctr, Parker Inst Canc Immunotherapy, Houston, TX 77030 USA. [Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. RP Wei, SC; Allison, JP (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA.; Allison, JP (reprint author), Univ Texas MD Anderson Canc Ctr, Parker Inst Canc Immunotherapy, Houston, TX 77030 USA. EM scwei@mdanderson.org; jallison@mdanderson.org EM scwei@mdanderson.org; jallison@mdanderson.org OI Cogdill, Alexandria/0000-0001-8917-9462; Pe'er, Dana/0000-0002-9259-8817; Anang, Nana-Ama/0000-0002-8495-2978; Allison, James/0000-0001-8980-5697; Wei, Spencer/0000-0001-9673-9683; Andrews, Miles/0000-0003-1231-8641 FU NCI Cancer Center Support Grant (CCSG) [P30CA016672]; Cancer Prevention and Research Institute of Texas (CPRIT) [R1203]; MDACC CCSG Bioinformatics Shared Resource [P30CA016672]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DP1-HD084071, R01CA164729, R01CA163793]; MSK Cancer Center Support Grant/Core Grant [P30CA008748] FX We thank Duncan Mak for expert advice and technical assistance with mass cytometry analysis. Mass cytometry and cell sorting were performed at the MDACC Flow Cytometry and Cellular Imaging Core Facility, which is in part funded by NCI Cancer Center Support Grant (CCSG) P30CA016672. Sequencing was performed at the MDACC Sequencing and Microarray Facility, which is also in part funded by P30CA016672(SMF). This work was supported by a grant from Cancer Prevention and Research Institute of Texas (CPRIT) to J.P.A. (R1203), the MDACC CCSG Bioinformatics Shared Resource (P30CA016672 39), NIH grants to D.P. (DP1-HD084071 and R01CA164729), and a MSK Cancer Center Support Grant/Core Grant to D.P. (P30CA008748). S.C.W. is an MDACC Odyssey postdoctoral fellow. J.P.A. and P.S. are co-directors, and J.A.W. is a member of the Parker Institute for Cancer Immunotherapy. P.S. has consulted for AstraZeneca, Amgen, GlaxoSmithKline (GSK), and Bristol-Myers Squibb (BMS). P.S. serves on the scientific advisory boards for Jounce, Neon, Constellation, and Kite. P.S. is a co-founder of Jounce Therapeutics. P.S. received funding on NIH R01CA163793. M.C.A. has attended speakers' bureau with travel support from BMS and MSD. J.A.W. has received honoraria from speakers' bureau of Dava Oncology, BMS, and Illumina and is an advisory board member for GSK, Novartis, and Roche/Genentech. J.P.A. is a co-founder of Jounce and Neon Therapeutics, is an advisory board member for Jounce, Neon, Amgen, and Kite Pharmaceuticals, and has received royalties from intellectual property licensed to BMS and Merck. 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McGovern, Naomi Sichien, Dorine Chakarov, Svetoslav Van Gassen, Sofie Chen, Jinmiao Poidinger, Michael De Prijck, Sofie Tavernier, Simon J. Low, Ivy Irac, Sergio Erdal Mattar, Citra Nurfarah Sumatoh, Hermi Rizal Low, Gillian Hui Ling Chung, Tam John Kit Chan, Dedrick Kok Hong Tan, Ker Kan Hon, Tony Lim Kiat Fossum, Even Bogen, Bjame Choolani, Mahesh Chan, Jerry Kok Yen Larbi, Anis Luche, Herve Henri, Sandrine Saeys, Yvan Newell, Evan William Lambrecht, Bart N. Malissen, Bernard Ginhoux, Florent TI Unsupervised High-Dimensional Analysis Aligns Dendritic Cells across Tissues and Species SO IMMUNITY LA English DT Article ID CLONOGENIC PROGENITOR; SIGNALING CONTROLS; STEADY-STATE; LYMPH-NODES; BONE-MARROW; MACROPHAGES; EXPRESSION; RESPONSES; BLOOD; HOMEOSTASIS AB Dendritic cells (DCs) are professional antigen-presenting cells that hold great therapeutic potential. Multiple DC subsets have been described, and it remains challenging to align them across tissues and species to analyze their function in the absence of macrophage contamination. Here, we provide and validate a universal toolbox for the automated identification of DCs through unsupervised analysis of conventional flow cytometry and mass cytometry data obtained from multiple mouse, macaque, and human tissues. The use of a minimal set of lineage-imprinted markers was sufficient to subdivide DCs into conventional type 1 (cDC1s), conventional type 2 (cDC2s), and plasmacytoid DCs (pDCs) across tissues and species. This way, a large number of additional markers can still be used to further characterize the heterogeneity of DCs across tissues and during inflammation. This framework represents the way forward to a universal, high-throughput, and standardized analysis of DC populations from mutant mice and human patients. C1 [Guilliams, Martin; Scott, Charlotte L.; Sichien, Dorine; De Prijck, Sofie; Tavernier, Simon J.; Lambrecht, Bart N.] VIB Inflammat Res Ctr, Unit Immunoregulat & Mucosal Immunol, B-9052 Ghent, Belgium. [Guilliams, Martin; Scott, Charlotte L.; Sichien, Dorine] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. [Guilliams, Martin; Luche, Herve; Henri, Sandrine; Malissen, Bernard] Aix Marseille Univ, CNRS, INSERM, Ctr Immunol Marseille Luminy, F-13288 Marseille, France. [Dutertre, Charles-Antoine; McGovern, Naomi; Chakarov, Svetoslav; Chen, Jinmiao; Poidinger, Michael; Low, Ivy; Sumatoh, Hermi Rizal; Low, Gillian Hui Ling; Chan, Jerry Kok Yen; Larbi, Anis; Newell, Evan William; Ginhoux, Florent] ASTAR, Singapore Immunol Network SIgN, BIOPOLIS, 8A Biomed Grove,IMMUNOS Bldg 3-4, Singapore 138648, Singapore. [Dutertre, Charles-Antoine; Irac, Sergio Erdal] Duke NUS Med Sch, Program Emerging Infect Dis, 8 Coll Rd, Singapore 169857, Singapore. [Van Gassen, Sofie] Univ Ghent, Dept Informat Technol, iMinds, B-9000 Ghent, Belgium. [Van Gassen, Sofie; Saeys, Yvan] VIB Inflammat Res Ctr, Data Min & Modeling Biomed, B-9052 Ghent, Belgium. [De Prijck, Sofie; Tavernier, Simon J.; Saeys, Yvan; Lambrecht, Bart N.] Univ Ghent, Dept Internal Med, B-9000 Ghent, Belgium. [Mattar, Citra Nurfarah; Choolani, Mahesh; Chan, Jerry Kok Yen] Natl Univ Singapore, Yong Loo Lin Sch Med, Expt Fetal Med Grp, Singapore 119077, Singapore. [Chung, Tam John Kit; Chan, Dedrick Kok Hong; Tan, Ker Kan] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 119077, Singapore. [Hon, Tony Lim Kiat] Natl Univ Singapore, Dept Pathol, Singapore 119077, Singapore. [Fossum, Even; Bogen, Bjame] Univ Oslo, Oslo Univ Hosp, KG Jebsen Ctr Influenza Vaccine Res, N-0027 Oslo, Norway. [Bogen, Bjame] Univ Oslo, Oslo Univ Hosp, Rikshosp, Inst Immunol,Ctr Immune Regulat, N-0424 Oslo, Norway. [Chan, Jerry Kok Yen] KK Womens & Childrens Hosp, Dept Reprod Med, Div Obstet & Gynaecol, Singapore 229899, Singapore. [Chan, Jerry Kok Yen] Duke NUS Grad Med Sch, Canc & Stem Cell Biol Program, Singapore 119077, Singapore. [Luche, Herve; Malissen, Bernard] Aix Marseille Univ, CNRS, Ctr Immunophenom, INSERM, F-13288 Marseille, France. [Lambrecht, Bart N.] Erasmus MC, Dept Pulm Med, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. C1 [Guilliams, Martin; Scott, Charlotte L.; Sichien, Dorine; De Prijck, Sofie; Tavernier, Simon J.; Lambrecht, Bart N.] VIB Inflammat Res Ctr, Unit Immunoregulat & Mucosal Immunol, B-9052 Ghent, Belgium. [Guilliams, Martin; Scott, Charlotte L.; Sichien, Dorine] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium. [Guilliams, Martin; Luche, Herve; Henri, Sandrine; Malissen, Bernard] Aix Marseille Univ, CNRS, INSERM, Ctr Immunol Marseille Luminy, F-13288 Marseille, France. [Dutertre, Charles-Antoine; McGovern, Naomi; Chakarov, Svetoslav; Chen, Jinmiao; Poidinger, Michael; Low, Ivy; Sumatoh, Hermi Rizal; Low, Gillian Hui Ling; Chan, Jerry Kok Yen; Larbi, Anis; Newell, Evan William; Ginhoux, Florent] ASTAR, Singapore Immunol Network SIgN, BIOPOLIS, 8A Biomed Grove,IMMUNOS Bldg 3-4, Singapore 138648, Singapore. [Dutertre, Charles-Antoine; Irac, Sergio Erdal] Duke NUS Med Sch, Program Emerging Infect Dis, 8 Coll Rd, Singapore 169857, Singapore. [Van Gassen, Sofie] Univ Ghent, Dept Informat Technol, iMinds, B-9000 Ghent, Belgium. [Van Gassen, Sofie; Saeys, Yvan] VIB Inflammat Res Ctr, Data Min & Modeling Biomed, B-9052 Ghent, Belgium. [De Prijck, Sofie; Tavernier, Simon J.; Saeys, Yvan; Lambrecht, Bart N.] Univ Ghent, Dept Internal Med, B-9000 Ghent, Belgium. [Mattar, Citra Nurfarah; Choolani, Mahesh; Chan, Jerry Kok Yen] Natl Univ Singapore, Yong Loo Lin Sch Med, Expt Fetal Med Grp, Singapore 119077, Singapore. [Chung, Tam John Kit; Chan, Dedrick Kok Hong; Tan, Ker Kan] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 119077, Singapore. [Hon, Tony Lim Kiat] Natl Univ Singapore, Dept Pathol, Singapore 119077, Singapore. [Fossum, Even; Bogen, Bjame] Univ Oslo, Oslo Univ Hosp, KG Jebsen Ctr Influenza Vaccine Res, N-0027 Oslo, Norway. [Bogen, Bjame] Univ Oslo, Oslo Univ Hosp, Rikshosp, Inst Immunol,Ctr Immune Regulat, N-0424 Oslo, Norway. [Chan, Jerry Kok Yen] KK Womens & Childrens Hosp, Dept Reprod Med, Div Obstet & Gynaecol, Singapore 229899, Singapore. [Chan, Jerry Kok Yen] Duke NUS Grad Med Sch, Canc & Stem Cell Biol Program, Singapore 119077, Singapore. [Luche, Herve; Malissen, Bernard] Aix Marseille Univ, CNRS, Ctr Immunophenom, INSERM, F-13288 Marseille, France. [Lambrecht, Bart N.] Erasmus MC, Dept Pulm Med, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. RP Guilliams, M; Lambrecht, BN (reprint author), VIB Inflammat Res Ctr, Unit Immunoregulat & Mucosal Immunol, B-9052 Ghent, Belgium.; Guilliams, M (reprint author), Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium.; Guilliams, M; Malissen, B (reprint author), Aix Marseille Univ, CNRS, INSERM, Ctr Immunol Marseille Luminy, F-13288 Marseille, France.; Ginhoux, F (reprint author), ASTAR, Singapore Immunol Network SIgN, BIOPOLIS, 8A Biomed Grove,IMMUNOS Bldg 3-4, Singapore 138648, Singapore.; Lambrecht, BN (reprint author), Univ Ghent, Dept Internal Med, B-9000 Ghent, Belgium.; Malissen, B (reprint author), Aix Marseille Univ, CNRS, Ctr Immunophenom, INSERM, F-13288 Marseille, France.; Lambrecht, BN (reprint author), Erasmus MC, Dept Pulm Med, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. EM martin.guilliams@irc.vib-ugent.be; bart.lambrecht@irc.vib-ugent.be; bernardm@ciml.univ-mrs.fr; florent_ginhoux@immunol.a-star.edu.sg EM martin.guilliams@irc.vib-ugent.be; bart.lambrecht@irc.vib-ugent.be; bernardm@ciml.univ-mrs.fr; florent_ginhoux@immunol.a-star.edu.sg RI Newell, Evan/AAE-9470-2020; Tavernier, Simon/L-9949-2019; Irac, Sergio Erdal/G-6690-2014; Tan, Ker Kan/K-2506-2017; Fossum, Even/W-9136-2019; Lambrecht, Bart N/K-2484-2014; Saeys, Yvan/C-1311-2009; Henri, Sandrine/O-3045-2016; Newell, Evan W/F-9711-2012; Tam, John/B-6048-2012; Chakarov, Svetoslav/AAC-9283-2019; Guilliams, Martin MG/N-7803-2013; Malissen, Bernard/AAK-4659-2020; Scott, Charlotte/K-3563-2014 OI Newell, Evan/0000-0002-2889-243X; Tavernier, Simon/0000-0003-2514-5655; Irac, Sergio Erdal/0000-0001-5622-1409; Tan, Ker Kan/0000-0002-0410-0450; Fossum, Even/0000-0001-7064-0327; Lambrecht, Bart N/0000-0003-4376-6834; Saeys, Yvan/0000-0002-0415-1506; Newell, Evan W/0000-0002-2889-243X; Chakarov, Svetoslav/0000-0002-0665-5417; Guilliams, Martin MG/0000-0003-3525-7570; Malissen, Bernard/0000-0003-1340-9342; Van Gassen, Sofie/0000-0002-7119-5330; Scott, Charlotte/0000-0003-4914-6580; Dutertre, Charles-Antoine/0000-0001-7950-3652; Poidinger, Michael/0000-0002-1047-2277; McGovern, Naomi/0000-0001-5200-2698; HENRI, Sandrine/0000-0002-8980-9193 FU Singapore Immunology NetworkAgency for Science Technology & Research (ASTAR); National Research Foundation Singapore under its cooperative basic research grant new investigator grant [NMRC/BNIG/2026/2014]; Marie Curie Intra-European Fellowship (IEF) as part of Horizon; Marie Curie Reintegration grantEuropean Union (EU); Odysseus grant; FWO grants of the Flemish Government; CNRSCentre National de la Recherche Scientifique (CNRS); INSERMInstitut National de la Sante et de la Recherche Medicale (Inserm); PHENOMIN; European Research Council (FP7) [322465]; Flanders Agency for Innovation by Science and Technology (IWT)Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT) FX We thank Gert Van Isterdael and Charlene Foong Shu Fen from the Flow Cytometry Core Platform of the IRC and SingHealth, respectively. This work was supported by core grants of the Singapore Immunology Network to F.G. and E.W.N. and by the National Research Foundation Singapore under its cooperative basic research grant new investigator grant (NMRC/BNIG/2026/2014) and administered by the Singapore Ministry of Health's National Medical Research Council to C.-A.D. C.L.S. is supported by a Marie Curie Intra-European Fellowship (IEF) as part of Horizon 2020. M.G. is supported by a Marie Curie Reintegration grant, an Odysseus grant, and FWO grants of the Flemish Government. B.M. is supported by the CNRS, INSERM, PHENOMIN, and European Research Council (FP7/2007-2013 grant no 322465). S.V.G. is funded by the Flanders Agency for Innovation by Science and Technology (IWT). 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Jager, Astraea Krishnaswamy, Smita Sachs, Karen Fantl, Wendy Pe'er, Dana Nolan, Garry P. Bendall, Sean C. TI Normalization of mass cytometry data with bead standards SO CYTOMETRY PART A LA English DT Article DE mass cytometry; CyTOF; normalization; blood; PBMC; flow cytometry; phenotype; internal standards AB Mass cytometry uses atomic mass spectrometry combined with isotopically pure reporter elements to currently measure as many as 40 parameters per single cell. As with any quantitative technology, there is a fundamental need for quality assurance and normalization protocols. In the case of mass cytometry, the signal variation over time due to changes in instrument performance combined with intervals between scheduled maintenance must be accounted for and then normalized. Here, samples were mixed with polystyrene beads embedded with metal lanthanides, allowing monitoring of mass cytometry instrument performance over multiple days of data acquisition. The protocol described here includes simultaneous measurements of beads and cells on the mass cytometer, subsequent extraction of the bead-based signature, and the application of an algorithm enabling correction of both short- and long-term signal fluctuations. The variation in the intensity of the beads that remains after normalization may also be used to determine data quality. Application of the algorithm to a one-month longitudinal analysis of a human peripheral blood sample reduced the range of median signal fluctuation from 4.9-fold to 1.3-fold. (c) 2013 International Society for Advancement of Cytometry C1 [Finck, Rachel; Simonds, Erin F.; Jager, Astraea; Sachs, Karen; Fantl, Wendy; Nolan, Garry P.; Bendall, Sean C.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Krishnaswamy, Smita; Pe'er, Dana] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. C1 [Finck, Rachel; Simonds, Erin F.; Jager, Astraea; Sachs, Karen; Fantl, Wendy; Nolan, Garry P.; Bendall, Sean C.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Krishnaswamy, Smita; Pe'er, Dana] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. RP Nolan, GP (reprint author), Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. EM gnolan@stanford.edu; bendall@stanford.edu EM gnolan@stanford.edu; bendall@stanford.edu RI Nolan, Garry/AAE-7903-2019; Krishnaswamy, Smita/D-8089-2016 OI Krishnaswamy, Smita/0000-0001-5823-1985; Simonds, Erin/0000-0002-3497-4861; Pe'er, Dana/0000-0002-9259-8817 FU Damon Runyon Cancer Research Foundation [DRG-2017-09]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [PN2EY018228, 0158 G KB065, U19 AI057229, P01 CA034233-22A1, HHSN272200700038C, 1R01CA130826, RFA CA 09-011, RFA CA 09-009]; CIRMCalifornia Institute for Regenerative Medicine [USC DR1-01477] FX Grant sponsor: Damon Runyon Cancer Research Foundation Fellowship; Grant number: DRG-2017-09; Grant sponsor: NIH; Grant numbers: PN2EY018228, 0158 G KB065, U19 AI057229, P01 CA034233-22A1, HHSN272200700038C, 1R01CA130826, RFA CA 09-011, and RFA CA 09-009; Grant sponsor: CIRM grant; Grant number: USC DR1-01477. CR Abdelrahman AI, 2010, J ANAL ATOM SPECTROM, V25, P260, DOI 10.1039/b921770c Abdelrahman AI, 2009, J AM CHEM SOC, V131, P15276, DOI 10.1021/ja9052009 Bandura DR, 2009, ANAL CHEM, V81, P6813, DOI 10.1021/ac901049w Bendall SC, 2011, SCIENCE, V332, P687, DOI 10.1126/science.1198704 Bodenmiller B, 2012, NAT BIOTECHNOL, V30, P858, DOI 10.1038/nbt.2317 Dendrou Calliope A., 2009, Advances in Bioinformatics, V2009, P476106, DOI 10.1155/2009/476106 Hahne F, 2010, CYTOM PART A, V77A, P121, DOI 10.1002/cyto.a.20823 Ornatsky O, 2010, J IMMUNOL METHODS, V361, P1, DOI 10.1016/j.jim.2010.07.002 Perfetto SP, 2006, NAT PROTOC, V1, P1522, DOI 10.1038/nprot.2006.250 NR 9 TC 254 Z9 253 U1 6 U2 51 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2013 VL 83A IS 5 BP 483 EP + DI 10.1002/cyto.a.22271 PG 12 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 133CW UT WOS:000318116000001 PM 23512433 OA Green Accepted DA 2020-07-01 ER PT J AU Horowitz, A Strauss-Albee, DM Leipold, M Kubo, J Nemat-Gorgani, N Dogan, OC Dekker, CL Mackey, S Maecker, H Swan, GE Davis, MM Norman, PJ Guethlein, LA Desai, M Parham, P Blish, CA AF Horowitz, Amir Strauss-Albee, Dara M. Leipold, Michael Kubo, Jessica Nemat-Gorgani, Neda Dogan, Ozge C. Dekker, Cornelia L. Mackey, Sally Maecker, Holden Swan, Gary E. Davis, Mark M. Norman, Paul J. Guethlein, Lisbeth A. Desai, Manisha Parham, Peter Blish, Catherine A. TI Genetic and Environmental Determinants of Human NK Cell Diversity Revealed by Mass Cytometry SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NATURAL-KILLER-CELLS; HLA-C; INHIBITORY RECEPTORS; CYTOMEGALOVIRUS-INFECTION; MISSING SELF; SPECIFICITY; REPERTOIRES; ACTIVATION; KIR; CYTOTOXICITY AB Natural killer (NK) cells play critical roles in immune defense and reproduction, yet remain the most poorly understood major lymphocyte population. Because their activation is controlled by a variety of combinatorially expressed activating and inhibitory receptors, NK cell diversity and function are closely linked. To provide an unprecedented understanding of NK cell repertoire diversity, we used mass cytometry to simultaneously analyze 37 parameters, including 28 NK cell receptors, on peripheral blood NK cells from 5 sets of monozygotic twins and 12 unrelated donors of defined human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genotype. This analysis revealed a remarkable degree of NK cell diversity, with an estimated 6000 to 30,000 phenotypic populations within an individual and >100,000 phenotypes in the donor panel. Genetics largely determined inhibitory receptor expression, whereas activation receptor expression was heavily environmentally influenced. Therefore, NK cells may maintain self-tolerance through strictly regulated expression of inhibitory receptors while using adaptable expression patterns of activating and costimulatory receptors to respond to pathogens and tumors. These findings further suggest the possibility that discrete NK cell subpopulations could be harnessed for immunotherapeutic strategies in the settings of infection, reproduction, and transplantation. C1 [Horowitz, Amir; Nemat-Gorgani, Neda; Norman, Paul J.; Guethlein, Lisbeth A.; Parham, Peter] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. [Horowitz, Amir; Leipold, Michael; Maecker, Holden; Davis, Mark M.; Parham, Peter] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Horowitz, Amir; Strauss-Albee, Dara M.; Davis, Mark M.; Parham, Peter; Blish, Catherine A.] Stanford Univ, Sch Med, Stanford Immunol, Stanford, CA 94305 USA. [Strauss-Albee, Dara M.; Kubo, Jessica; Dogan, Ozge C.; Desai, Manisha; Blish, Catherine A.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Dekker, Cornelia L.; Mackey, Sally] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. [Swan, Gary E.] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. C1 [Horowitz, Amir; Nemat-Gorgani, Neda; Norman, Paul J.; Guethlein, Lisbeth A.; Parham, Peter] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. [Horowitz, Amir; Leipold, Michael; Maecker, Holden; Davis, Mark M.; Parham, Peter] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Horowitz, Amir; Strauss-Albee, Dara M.; Davis, Mark M.; Parham, Peter; Blish, Catherine A.] Stanford Univ, Sch Med, Stanford Immunol, Stanford, CA 94305 USA. [Strauss-Albee, Dara M.; Kubo, Jessica; Dogan, Ozge C.; Desai, Manisha; Blish, Catherine A.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Dekker, Cornelia L.; Mackey, Sally] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. [Swan, Gary E.] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. RP Blish, CA (reprint author), Stanford Univ, Sch Med, Stanford Immunol, Stanford, CA 94305 USA. EM cblish@stanford.edu EM cblish@stanford.edu RI Leipold, Michael/A-9452-2013 OI Leipold, Michael/0000-0001-5389-0906; Blish, Catherine/0000-0001-6946-7627; Strauss-Albee, Dara/0000-0003-1235-7800; Norman, Paul/0000-0001-8370-7703 FU NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [T32 AI07290, AI22039, U19AI090019, U19 AI057229]; NSFNational Science Foundation (NSF) [DGE-114740]; NIH/National Center for Research Resources Clinical and Translational Science Award [UL1 RR025744]; University of Washington Center for AIDS Research [P30 AI027757]; Beckman Young Investigator Award FX This study was funded by NIH training grant T32 AI07290 (A. H.), NSF training grant DGE-114740 (D. M. S.-A.), NIH grants AI22039 (P. P.) and U19AI090019 and U19 AI057229 (M. M. D.), NIH/National Center for Research Resources Clinical and Translational Science Award UL1 RR025744, a New Investigator Award from the University of Washington Center for AIDS Research (P30 AI027757, C. A. B.), and a Beckman Young Investigator Award (C.A.B.). 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Transl. Med. PD OCT 23 PY 2013 VL 5 IS 208 AR 208ra145 DI 10.1126/scitranslmed.3006702 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 240IX UT WOS:000326090200006 PM 24154599 OA Green Accepted DA 2020-07-01 ER PT J AU Chevrier, S Levine, JH Zanotelli, VRT Silina, K Schulz, D Bacac, M Ries, CH Ailles, L Jewett, MAS Moch, H van den Broek, M Beisel, C Stadler, MB Gedye, C Reis, B Pe'er, D Bodenmiller, B AF Chevrier, Stephane Levine, Jacob Harrison Zanotelli, Vito Riccardo Tomaso Silina, Karina Schulz, Daniel Bacac, Marina Ries, Carola Hermine Ailles, Laurie Jewett, Michael Alexander Spencer Moch, Holger van den Broek, Maries Beisel, Christian Stadler, Michael Beda Gedye, Craig Reis, Bernhard Pe'er, Dana Bodenmiller, Bernd TI An Immune Atlas of Clear Cell Renal Cell Carcinoma SO CELL LA English DT Article ID TUMOR-ASSOCIATED MACROPHAGES; T-CELLS; GLIOMA PROGRESSION; CANCER; POLARIZATION; EXPRESSION; ACTIVATION; REVEALS; CD38; MECHANISMS AB Immune cells in the tumor microenvironment modulate cancer progression and are attractive therapeutic targets. Macrophages and T cells are key components of the microenvironment, yet their phenotypes and relationships in this ecosystem and to clinical outcomes are ill defined. We used mass cytometry with extensive antibody panels to perform in-depth immune profiling of samples from 73 clear cell renal cell carcinoma (ccRCC) patients and five healthy controls. In 3.5 million measured cells, we identified 17 tumor-associated macrophage phenotypes, 22 T cell phenotypes, and a distinct immune composition correlated with progression-free survival, thereby presenting an in-depth human atlas of the immune tumor microenvironment in this disease. This study revealed potential biomarkers and targets for immunotherapy development and validated tools that can be used for immune profiling of other tumor types. C1 [Chevrier, Stephane; Zanotelli, Vito Riccardo Tomaso; Schulz, Daniel; Bodenmiller, Bernd] Univ Zurich, Inst Mol Life Sci, Winterthurerstr 190, CH-8057 Zurich, Switzerland. [Levine, Jacob Harrison; Pe'er, Dana] Sloan Kettering Inst, Computat & Syst Biol Program, 1275 York Ave, New York, NY 10065 USA. [Zanotelli, Vito Riccardo Tomaso] ETH, Syst Biol PhD Program, Life Sci Zurich Grad Sch, CH-8057 Zurich, Switzerland. [Zanotelli, Vito Riccardo Tomaso] Univ Zurich, CH-8057 Zurich, Switzerland. [Silina, Karina; van den Broek, Maries] Univ Zurich, Inst Expt Immunol, Winterthurerstr 190, CH-8057 Zurich, Switzerland. [Bacac, Marina] Roche Innovat Ctr Zurich, Roche Pharma Res & Early Dev, Wagistr 18, CH-8952 Schlieren, Switzerland. [Ries, Carola Hermine] Roche Innovat Ctr Zurich, Roche Pharma Res & Early Dev, Nonnenwald 2, D-82377 Penzberg, Germany. [Ailles, Laurie] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada. [Ailles, Laurie; Jewett, Michael Alexander Spencer] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada. [Moch, Holger] Univ Hosp Zurich, Inst Surg Pathol, Schmelzbergstr 12, CH-8091 Zurich, Switzerland. [Beisel, Christian] ETH, Dept Biosyst Sci & Engn, Mattenstr 26, CH-4058 Basel, Switzerland. [Stadler, Michael Beda] Friedrich Miescher Inst Biomed Res, Maulbeerstr 66, CH-4058 Basel, Switzerland. [Stadler, Michael Beda] Swiss Inst Bioinformat, Mattenstr 26, CH-4058 Basel, Switzerland. [Gedye, Craig] Univ Newcastle, Hunter Med Res Inst, Sch Biomed Sci & Pharm, Newcastle, NSW 2035, Australia. [Reis, Bernhard] Roche Innovat Ctr Basel, Pharmaceut Sci, Roche Pharma Res & Early Dev, Grenzacherstr 124, CH-4070 Basel, Switzerland. C1 [Chevrier, Stephane; Zanotelli, Vito Riccardo Tomaso; Schulz, Daniel; Bodenmiller, Bernd] Univ Zurich, Inst Mol Life Sci, Winterthurerstr 190, CH-8057 Zurich, Switzerland. [Levine, Jacob Harrison; Pe'er, Dana] Sloan Kettering Inst, Computat & Syst Biol Program, 1275 York Ave, New York, NY 10065 USA. [Zanotelli, Vito Riccardo Tomaso] ETH, Syst Biol PhD Program, Life Sci Zurich Grad Sch, CH-8057 Zurich, Switzerland. [Zanotelli, Vito Riccardo Tomaso] Univ Zurich, CH-8057 Zurich, Switzerland. [Silina, Karina; van den Broek, Maries] Univ Zurich, Inst Expt Immunol, Winterthurerstr 190, CH-8057 Zurich, Switzerland. [Bacac, Marina] Roche Innovat Ctr Zurich, Roche Pharma Res & Early Dev, Wagistr 18, CH-8952 Schlieren, Switzerland. [Ries, Carola Hermine] Roche Innovat Ctr Zurich, Roche Pharma Res & Early Dev, Nonnenwald 2, D-82377 Penzberg, Germany. [Ailles, Laurie] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada. [Ailles, Laurie; Jewett, Michael Alexander Spencer] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada. [Moch, Holger] Univ Hosp Zurich, Inst Surg Pathol, Schmelzbergstr 12, CH-8091 Zurich, Switzerland. [Beisel, Christian] ETH, Dept Biosyst Sci & Engn, Mattenstr 26, CH-4058 Basel, Switzerland. [Stadler, Michael Beda] Friedrich Miescher Inst Biomed Res, Maulbeerstr 66, CH-4058 Basel, Switzerland. [Stadler, Michael Beda] Swiss Inst Bioinformat, Mattenstr 26, CH-4058 Basel, Switzerland. [Gedye, Craig] Univ Newcastle, Hunter Med Res Inst, Sch Biomed Sci & Pharm, Newcastle, NSW 2035, Australia. [Reis, Bernhard] Roche Innovat Ctr Basel, Pharmaceut Sci, Roche Pharma Res & Early Dev, Grenzacherstr 124, CH-4070 Basel, Switzerland. RP Bodenmiller, B (reprint author), Univ Zurich, Inst Mol Life Sci, Winterthurerstr 190, CH-8057 Zurich, Switzerland. EM bernd.bodenmiller@imls.uzh.ch EM bernd.bodenmiller@imls.uzh.ch RI van den Broek, Maries/L-6532-2019; wang, edwin/G-5372-2010 OI Gedye, Craig/0000-0002-1629-4352; Zanotelli, Vito Riccardo Tomaso/0000-0001-7268-311X; van den Broek, Maries/0000-0002-9489-3692; Pe'er, Dana/0000-0002-9259-8817; Reis, Bernhard/0000-0001-7611-8222 FU SNSFSwiss National Science Foundation (SNSF); SystemsX Transfer Project "Friends and Foes"; SystemsX MetastasiX grant; European Research Council (ERC) under the European Union/ERCEuropean Research Council (ERC) [336921]; RocheRoche Holding; EMBO - European Commission [ALTF 970-2014, GA-2013-609409]; RACP CSL Fellowship; CIHR/KCC SHOPP Fellowship; NHMRCNational Health and Medical Research Council of Australia [628939]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DP1-HD084071, R01CA164729]; SNSFSwiss National Science Foundation (SNSF) [31003A_152851]; Zurich Cancer League grant; Stiftung fur Forschung in der Onkologie grant; University Research Priority Project "Translational Cancer Research" grant; MSK Cancer Center [P30 CA008748]; F. Hoffmann-La Roche AGHoffmann-La Roche FX We are very grateful for the generous donation of tumor samples by patients undergoing surgery that was collected through the University Health Network Biobank and Cooperative Health Tissue Network. We thank Manfred Kopf, Luigi Tortola, Sabine Hoves, Sylvia Herter, and the Bodenmiller lab for fruitful discussions; Andrew Evans for pathological analysis of tissue samples; Andrea Jacobs and Stefanie Engler for technical support; Christina Ewald for cell sorting; the CyTOF facility and the Center for Microscopy and Image Analysis (University of Zurich); and the Genomics Facility Basel. B.B.'s research is funded by a SNSF R'Equip grant, a SNSF Assistant Professorship grant, the SystemsX Transfer Project "Friends and Foes," the SystemsX MetastasiX grant, and the European Research Council (ERC) under the European Union's Seventh Framework Program (FP/2007-2013/ERC grant agreement no. 336921). This work was funded by a Roche Postdoctoral Fellowship (to S.C.); an EMBO fellowship (ALTF 970-2014) co-funded by the European Commission (LTFCOFUND2013, GA-2013-609409) (to D.S.); an RACP CSL Fellowship (to C.G.); a CIHR/KCC SHOPP Fellowship (to C.G.), an NHMRC Early Career Fellowship (628939 to C.G.), NIH grants (DP1-HD084071 and R01CA164729), a SNSF grant (31003A_152851 to M.v.d.B.), a Zurich Cancer League grant (to M.v.d.B. and K.S.), a Stiftung fur Forschung in der Onkologie grant (to M.v.d.B.), a University Research Priority Project "Translational Cancer Research" grant (to M.v.d.B.), and a MSK Cancer Center Support Grant/Core Grant (P30 CA008748) (to D.P.). This work was in part supported by a fellowship from F. Hoffmann-La Roche AG. M.B., C.R., and B.R. are employees for F. Hoffmann-La Roche AG. 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Carmi, Yaron Reticker-Flynn, Nathan E. Kwek, Serena S. Madhireddy, Deepthi Martins, Maria M. Gherardini, Pier Federico Prestwood, Tyler R. Chabon, Jonathan Bendall, Sean C. Fong, Lawrence Nolan, Garry P. Engleman, Edgar G. TI Systemic Immunity Is Required for Effective Cancer Immunotherapy SO CELL LA English DT Article ID REGULATORY T-CELLS; MASS CYTOMETRY; BREAST-CANCER; TUMOR; IDENTIFICATION; PATIENT AB Immune responses involve coordination across cell types and tissues. However, studies in cancer immunotherapy have focused heavily on local immune responses in the tumor microenvironment. To investigate immune activity more broadly, we performed an organism-wide study in genetically engineered cancer models using mass cytometry. We analyzed immune responses in several tissues after immunotherapy by developing intuitive models for visualizing single-cell data with statistical inference. Immune activation was evident in the tumor and systemically shortly after effective therapy was administered. However, during tumor rejection, only peripheral immune cells sustained their proliferation. This systemic response was coordinated across tissues and required for tumor eradication in several immunotherapy models. An emergent population of peripheral CD4 T cells conferred protection against new tumors and was significantly expanded in patients responding to immunotherapy. These studies demonstrate the critical impact of systemic immune responses that drive tumor rejection. C1 [Spitzer, Matthew H.; Carmi, Yaron; Reticker-Flynn, Nathan E.; Martins, Maria M.; Prestwood, Tyler R.; Chabon, Jonathan; Bendall, Sean C.; Engleman, Edgar G.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Spitzer, Matthew H.; Madhireddy, Deepthi; Gherardini, Pier Federico; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Spitzer, Matthew H.; Nolan, Garry P.; Engleman, Edgar G.] Stanford Univ, Program Immunol, Stanford, CA 94305 USA. [Spitzer, Matthew H.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Kwek, Serena S.; Fong, Lawrence] Univ Calif San Francisco, Dept Med, Div Hematol & Oncol, San Francisco, CA 94143 USA. [Spitzer, Matthew H.; Fong, Lawrence] Univ Calif San Francisco, Helen Diller Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Carmi, Yaron] Tel Aviv Univ, Sackler Sch Med, Dept Pathol, IL-69978 Ramat Aviv, Israel. C1 [Spitzer, Matthew H.; Carmi, Yaron; Reticker-Flynn, Nathan E.; Martins, Maria M.; Prestwood, Tyler R.; Chabon, Jonathan; Bendall, Sean C.; Engleman, Edgar G.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Spitzer, Matthew H.; Madhireddy, Deepthi; Gherardini, Pier Federico; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Spitzer, Matthew H.; Nolan, Garry P.; Engleman, Edgar G.] Stanford Univ, Program Immunol, Stanford, CA 94305 USA. [Spitzer, Matthew H.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Kwek, Serena S.; Fong, Lawrence] Univ Calif San Francisco, Dept Med, Div Hematol & Oncol, San Francisco, CA 94143 USA. [Spitzer, Matthew H.; Fong, Lawrence] Univ Calif San Francisco, Helen Diller Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Carmi, Yaron] Tel Aviv Univ, Sackler Sch Med, Dept Pathol, IL-69978 Ramat Aviv, Israel. RP Spitzer, MH; Engleman, EG (reprint author), Stanford Univ, Dept Pathol, Stanford, CA 94305 USA.; Spitzer, MH; Nolan, GP (reprint author), Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA.; Spitzer, MH; Nolan, GP; Engleman, EG (reprint author), Stanford Univ, Program Immunol, Stanford, CA 94305 USA.; Spitzer, MH (reprint author), Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA.; Spitzer, MH (reprint author), Univ Calif San Francisco, Helen Diller Comprehens Canc Ctr, San Francisco, CA 94143 USA. EM matthew.spitzer@ucsf.edu; gnolan@stanford.edu; edengleman@stanford.edu EM matthew.spitzer@ucsf.edu; gnolan@stanford.edu; edengleman@stanford.edu RI Reticker-Flynn, Nathan/R-7226-2019; Nolan, Garry/AAE-7903-2019 OI Reticker-Flynn, Nathan/0000-0002-9963-039X; Spitzer, Matthew/0000-0002-5291-3819 FU NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [F31CA189331, DP5OD023056, F32CA189408, U19AI057229, U19AI100627, R33CA183654, R01HL120724, R01CA196657, U54CA209971, R01AI118884]; DODUnited States Department of Defense [OC110674, 11491122]; Gates FoundationGates Foundation [OPP1113682]; NIAIDUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [HHSN272201200028C]; FDAUnited States Department of Health & Human Services [HHSF223201210194C BAA-12-00118] FX We thank G.K. Fragiadakis and L.E. Sanman for helpful conversations and feedback and A. Trejo and A. Jager for CyTOF maintenance. M.H.S., P.F.G., L.F., and G.P.N. are investigators of the Parker Institute for Cancer Immunotherapy. G.P.N. has a personal financial interest in, and S.C.B. has been a paid consultant for, Fluidigm, manufacturer of the mass cytometer utilized. E.G.E. is a founder and board member of Bolt Biotherapeutics, licensee of the therapy with alloIgG. This work was supported by NIH grants F31CA189331 and DP5OD023056 to M.H.S.; NIH grant F32CA189408 to N.R.F.; NIH grants U19AI057229, U19AI100627, R33CA183654, and R01HL120724, DOD grants OC110674 and 11491122, Gates Foundation grant OPP1113682, NIAID grant HHSN272201200028C, and FDA grant HHSF223201210194C BAA-12-00118 to G.P.N.; NIH grants R01CA196657 and U54CA209971 to G.P.N. and E.G.E.; and NIH grant R01AI118884 to E.G.E. 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Reich-Zeliger, Shlomit Ange, Omer Salame, Tomer Meir Kathail, Pooja Choi, Kristy Bendall, Sean Friedman, Nir Pe'er, Dana TI Wishbone identifies bifurcating developmental trajectories from single-cell data SO NATURE BIOTECHNOLOGY LA English DT Article ID GENE-EXPRESSION; TRANSCRIPTION FACTORS; DIFFUSION MAPS; RNA-SEQ; DIFFERENTIATION; TRANSFORMATION; HETEROGENEITY; MECHANISMS; LANDSCAPE; NETWORKS AB Recent single-cell analysis technologies offer an unprecedented opportunity to elucidate developmental pathways. Here we present Wishbone, an algorithm for positioning single cells along bifurcating developmental trajectories with high resolution. Wishbone uses multi-dimensional single-cell data, such as mass cytometry or RNA-Seq data, as input and orders cells according to their developmental progression, and it pinpoints bifurcation points by labeling each cell as pre-bifurcation or as one of two post-bifurcation cell fates. Using 30-channel mass cytometry data, we show that Wishbone accurately recovers the known stages of T-cell development in the mouse thymus, including the bifurcation point. We also apply the algorithm to mouse myeloid differentiation and demonstrate its generalization to additional lineages. A comparison of Wishbone to diffusion maps, SCUBA and Monocle shows that it outperforms these methods both in the accuracy of ordering cells and in the correct identification of branch points. C1 [Setty, Manu; Tadmor, Michelle D.; Kathail, Pooja; Choi, Kristy; Pe'er, Dana] Columbia Univ, Dept Syst Biol, Dept Biol Sci, New York, NY USA. [Reich-Zeliger, Shlomit; Friedman, Nir] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. [Ange, Omer] Univ British Columbia, Dept Math, Vancouver, BC, Canada. [Salame, Tomer Meir] Weizmann Inst Sci, Biol Serv Unit, IL-76100 Rehovot, Israel. [Bendall, Sean] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. C1 [Setty, Manu; Tadmor, Michelle D.; Kathail, Pooja; Choi, Kristy; Pe'er, Dana] Columbia Univ, Dept Syst Biol, Dept Biol Sci, New York, NY USA. [Reich-Zeliger, Shlomit; Friedman, Nir] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. [Ange, Omer] Univ British Columbia, Dept Math, Vancouver, BC, Canada. [Salame, Tomer Meir] Weizmann Inst Sci, Biol Serv Unit, IL-76100 Rehovot, Israel. [Bendall, Sean] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. RP Pe'er, D (reprint author), Columbia Univ, Dept Syst Biol, Dept Biol Sci, New York, NY USA. EM dpeer@biology.columbia.edu EM dpeer@biology.columbia.edu OI Pe'er, Dana/0000-0002-9259-8817; Setty, Manu/0000-0002-0344-2627 FU NSFNational Science Foundation (NSF); NSFNational Science Foundation (NSF) [MCB-1149728]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DP1-HD084071, R01CA164729]; David and Fela Shapell Family Foundation INCPM Fund; Nissim Center, for the Development of Scientific Resources; ISFIsrael Science Foundation [1184/15] FX We would like to thank A. Bloemendal, Z. Good, N. Hacohen, S. Krishnaswamy, J. Levine and A.J. Carr for their helpful comments. M.D.T. is supported by an NSF graduate fellowship. This work was supported by NSF MCB-1149728, NIH DP1-HD084071, NIH R01CA164729 to D.P. D.P. holds a Packard Fellowship for Science and Engineering. This work was also supported by David and Fela Shapell Family Foundation INCPM Fund, the WIS staff scientists grant from the Nissim Center, for the Development of Scientific Resources, and ISF 1184/15 to N.F. 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Biotechnol. PD JUN PY 2016 VL 34 IS 6 BP 637 EP 645 DI 10.1038/nbt.3569 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DO5TT UT WOS:000377846400031 PM 27136076 OA Green Accepted DA 2020-07-01 ER PT J AU Rao, DA Gurish, MF Marshall, JL Slowikowski, K Fonseka, CY Liu, YY Donlin, LT Henderson, LA Wei, K Mizoguchi, F Teslovich, NC Weinblatt, ME Massarotti, EM Coblyn, JS Helfgott, SM Lee, YC Todd, DJ Ykerk, VPB Goodman, SM Pernis, AB Ivashkiv, LB Karlson, EW Nigrovic, PA Filer, A Buckley, CD Lederer, JA Raychaudhuri, S Renner, MBB AF Rao, Deepak A. Gurish, Michael F. Marshall, Jennifer L. Slowikowski, Kamil Fonseka, Chamith Y. Liu, Yanyan Donlin, Laura T. Henderson, Lauren A. Wei, Kevin Mizoguchi, Fumitaka Teslovich, Nikola C. Weinblatt, Michael E. Massarotti, Elena M. Coblyn, Jonathan S. Helfgott, Simon M. Lee, Yvonne C. Todd, Derrick J. Ykerk, Vivian P. B. Goodman, Susan M. Pernis, Alessandra B. Ivashkiv, Lionel B. Karlson, Elizabeth W. Nigrovic, Peter A. Filer, Andrew Buckley, Christopher D. Lederer, James A. Raychaudhuri, Soumya Renner, Michael B. B. TI Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis SO NATURE LA English DT Article ID FOLLICULAR HELPER; EXTRAVASATION; CXCL13; BCL6 AB CD4(+) T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4(+) T cells within affected tissues may be identified by expression of markers of recent activation(1). Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population(2). This approach revealed a markedly expanded population of PD-1(hi)CXCR5(-)CD4(+) T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1(hi)CXCR5(-) 'peripheral helper' T (T-PH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1(hi)CXCR5(+) T follicular helper cells, T-PH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between T-PH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in T-PH cells. T-PH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues. C1 [Rao, Deepak A.; Gurish, Michael F.; Slowikowski, Kamil; Fonseka, Chamith Y.; Liu, Yanyan; Henderson, Lauren A.; Wei, Kevin; Mizoguchi, Fumitaka; Teslovich, Nikola C.; Weinblatt, Michael E.; Karlson, Elizabeth W.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Wei, Kevin; Todd, Derrick J.; Goodman, Susan M.] Harvard Med Sch, Boston, MA 02115 USA. [Marshall, Jennifer L.; Henderson, Lauren A.; Helfgott, Simon M.; Todd, Derrick J.] Univ Birmingham, Queen Elizabeth Hosp, Inst Inflammat & Ageing, Rheumatol Res Grp, Birmingham B15 2WB, W Midlands, England. [Gurish, Michael F.; Liu, Yanyan; Lee, Yvonne C.; Goodman, Susan M.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Marshall, Jennifer L.; Donlin, Laura T.; Teslovich, Nikola C.; Helfgott, Simon M.; Lee, Yvonne C.] Harvard Med Sch, Boston, MA 02115 USA. [Slowikowski, Kamil; Todd, Derrick J.; Karlson, Elizabeth W.] MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02138 USA. [Rao, Deepak A.; Helfgott, Simon M.; Ykerk, Vivian P. B.; Karlson, Elizabeth W.] Harvard Univ, Cambridge, MA 02138 USA. [Fonseka, Chamith Y.] Partners Ctr Personalized Genet Med, Boston, MA 02115 USA. [Donlin, Laura T.; Henderson, Lauren A.] Harvard Univ, Bioinformat & Integrat Genom, Cambridge, MA 02138 USA. [Helfgott, Simon M.] Harvard Univ, Biol & Biomed Sci, Cambridge, MA 02138 USA. [Todd, Derrick J.; Karlson, Elizabeth W.] Hosp Special Surg, Arthrit & Tissue Degenerat Program, New York, NY USA. [Helfgott, Simon M.; Ivashkiv, Lionel B.; Buckley, Christopher D.; Raychaudhuri, Soumya] Hosp Special Surg, David Z Rosensweig Genom Res Ctr, New York, NY 10021 USA. [Marshall, Jennifer L.; Wei, Kevin; Coblyn, Jonathan S.; Lee, Yvonne C.; Ivashkiv, Lionel B.] Boston Childrens Hosp, Divis Immunol, Boston, MA 02115 USA. [Coblyn, Jonathan S.; Pernis, Alessandra B.; Nigrovic, Peter A.] Hosp Special Surg, Div Rheumatol, 535 E 70th St, New York, NY 10021 USA. [Slowikowski, Kamil; Mizoguchi, Fumitaka; Massarotti, Elena M.; Goodman, Susan M.] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Massarotti, Elena M.; Lee, Yvonne C.; Ykerk, Vivian P. B.; Pernis, Alessandra B.] Hosp Special Surg, Autoimmun & Inflammat Program, New York, NY 10021 USA. [Donlin, Laura T.; Goodman, Susan M.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Henderson, Lauren A.; Weinblatt, Michael E.; Goodman, Susan M.] Karolinska Inst, Reumatol Unit, S-17176 Stockholm, Sweden. [Mizoguchi, Fumitaka; Massarotti, Elena M.; Lee, Yvonne C.; Todd, Derrick J.] Karolinska Univ Hosp Solna, S-17176 Stockholm, Sweden. [Massarotti, Elena M.; Todd, Derrick J.; Ivashkiv, Lionel B.] Univ Manchester, Inst Inflammat & Repair, Manchester M13 9PT, Lancs, England. C1 [Rao, Deepak A.; Gurish, Michael F.; Slowikowski, Kamil; Fonseka, Chamith Y.; Liu, Yanyan; Henderson, Lauren A.; Wei, Kevin; Mizoguchi, Fumitaka; Teslovich, Nikola C.; Weinblatt, Michael E.; Karlson, Elizabeth W.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Wei, Kevin; Todd, Derrick J.; Goodman, Susan M.] Harvard Med Sch, Boston, MA 02115 USA. [Marshall, Jennifer L.; Henderson, Lauren A.; Helfgott, Simon M.; Todd, Derrick J.] Univ Birmingham, Queen Elizabeth Hosp, Inst Inflammat & Ageing, Rheumatol Res Grp, Birmingham B15 2WB, W Midlands, England. [Gurish, Michael F.; Liu, Yanyan; Lee, Yvonne C.; Goodman, Susan M.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Marshall, Jennifer L.; Donlin, Laura T.; Teslovich, Nikola C.; Helfgott, Simon M.; Lee, Yvonne C.] Harvard Med Sch, Boston, MA 02115 USA. [Slowikowski, Kamil; Todd, Derrick J.; Karlson, Elizabeth W.] MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02138 USA. [Rao, Deepak A.; Helfgott, Simon M.; Ykerk, Vivian P. B.; Karlson, Elizabeth W.] Harvard Univ, Cambridge, MA 02138 USA. [Fonseka, Chamith Y.] Partners Ctr Personalized Genet Med, Boston, MA 02115 USA. [Donlin, Laura T.; Henderson, Lauren A.] Harvard Univ, Bioinformat & Integrat Genom, Cambridge, MA 02138 USA. [Helfgott, Simon M.] Harvard Univ, Biol & Biomed Sci, Cambridge, MA 02138 USA. [Todd, Derrick J.; Karlson, Elizabeth W.] Hosp Special Surg, Arthrit & Tissue Degenerat Program, New York, NY USA. [Helfgott, Simon M.; Ivashkiv, Lionel B.; Buckley, Christopher D.; Raychaudhuri, Soumya] Hosp Special Surg, David Z Rosensweig Genom Res Ctr, New York, NY 10021 USA. [Marshall, Jennifer L.; Wei, Kevin; Coblyn, Jonathan S.; Lee, Yvonne C.; Ivashkiv, Lionel B.] Boston Childrens Hosp, Divis Immunol, Boston, MA 02115 USA. [Coblyn, Jonathan S.; Pernis, Alessandra B.; Nigrovic, Peter A.] Hosp Special Surg, Div Rheumatol, 535 E 70th St, New York, NY 10021 USA. [Slowikowski, Kamil; Mizoguchi, Fumitaka; Massarotti, Elena M.; Goodman, Susan M.] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Massarotti, Elena M.; Lee, Yvonne C.; Ykerk, Vivian P. B.; Pernis, Alessandra B.] Hosp Special Surg, Autoimmun & Inflammat Program, New York, NY 10021 USA. [Donlin, Laura T.; Goodman, Susan M.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Henderson, Lauren A.; Weinblatt, Michael E.; Goodman, Susan M.] Karolinska Inst, Reumatol Unit, S-17176 Stockholm, Sweden. [Mizoguchi, Fumitaka; Massarotti, Elena M.; Lee, Yvonne C.; Todd, Derrick J.] Karolinska Univ Hosp Solna, S-17176 Stockholm, Sweden. [Massarotti, Elena M.; Todd, Derrick J.; Ivashkiv, Lionel B.] Univ Manchester, Inst Inflammat & Repair, Manchester M13 9PT, Lancs, England. RP Rao, DA (reprint author), Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. EM darao@partners.org; mbrenner@research.bwh.harvard.edu EM darao@partners.org; mbrenner@research.bwh.harvard.edu RI Mizoguchi, Fumitaka/Y-3271-2018; Donlin, Laura T/P-2483-2019; Slowikowski, Kamil/K-3728-2016 OI Mizoguchi, Fumitaka/0000-0002-3956-7122; Donlin, Laura T/0000-0002-1428-090X; Slowikowski, Kamil/0000-0002-2843-6370; Marshall, Jennifer/0000-0002-1727-8290; Raychaudhuri, Soumya/0000-0002-1901-8265; Rao, Deepak/0000-0001-9672-7746 FU William Docken Inflammatory Autoimmune Disease Fund; Mallinckrodt Research Fellowship; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5U01GM092691-05, 1U19 AI111224-01]; Doris Duke Charitable FoundationDoris Duke Charitable Foundation (DDCF) [2013097]; Rheumatology Research Foundation Scientist Development Award; Arthritis Research UKVersus Arthritis [19791, 18547]; Fundacion Bechara; [T32 AR007530-31]; [R01 AR064850-03]; [K01 AR066063]; [FP7-HEALTH-F2-2012-305549 EuroTEAM]; [P30 AR070253]; Arthritis Research UKVersus Arthritis [20088] FX This work was supported by T32 AR007530-31 and the William Docken Inflammatory Autoimmune Disease Fund (to M.B.B.), Mallinckrodt Research Fellowship (to D.A.R.), R01 AR064850-03 (to Y.C.L.), NIH 5U01GM092691-05, 1U19 AI111224-01 and Doris Duke Charitable Foundation Grant #2013097 (to S.R.), Rheumatology Research Foundation Scientist Development Award (to L.A.H.), K01 AR066063 (to L.T.D.), Arthritis Research UK programme grant # 19791 (to C.D.B.), and Arthritis Research UK Clinician Scientist Fellowship # 18547 (to A.F.). J.L.M was supported by the FP7-HEALTH-F2-2012-305549 EuroTEAM. P.A.N. was supported by P30 AR070253 and the Fundacion Bechara. We thank A. Chicoine and the BWH Human Immunology Center Flow Cytometry Core for assistance with cell sorting. 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H. Ng, Lai Guan Ginhoux, Florent Newell, Evan W. TI Dimensionality reduction for visualizing single-cell data using UMAP SO NATURE BIOTECHNOLOGY LA English DT Article ID ATLAS; CYTOMETRY AB Advances in single-cell technologies have enabled high-resolution dissection of tissue composition. Several tools for dimensionality reduction are available to analyze the large number of parameters generated in single-cell studies. Recently, a nonlinear dimensionality-reduction technique, uniform manifold approximation and projection (UMAP), was developed for the analysis of any type of high-dimensional data. Here we apply it to biological data, using three well-characterized mass cytometry and single-cell RNA sequencing datasets. Comparing the performance of UMAP with five other tools, we find that UMAP provides the fastest run times, highest reproducibility and the most meaningful organization of cell clusters. 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RP Newell, EW (reprint author), ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore.; Newell, EW (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. EM enewell@fredhutch.org EM enewell@fredhutch.org RI Newell, Evan/AAE-9470-2020; Ng, Lai Guan/E-5673-2011 OI Newell, Evan/0000-0002-2889-243X; Ng, Lai Guan/0000-0003-1905-3586; Ginhoux, Florent/0000-0002-2857-7755; Dutertre, Charles-Antoine/0000-0001-7950-3652 FU A-STAR/SIgN core funding; A-STAR/SIgN immunomonitoring platform funding FX We thank members of the Singapore Immunology Network and notably members of the E.W.N. laboratory. We thank S. Li, Y. Simoni, M. Chng, Y. Cheng, J. W. Lim and M. Fehlings for their insightful feedback. This study was funded by A-STAR/SIgN core funding and A-STAR/SIgN immunomonitoring platform funding. 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Biotechnol. PD JAN PY 2019 VL 37 IS 1 BP 38 EP + DI 10.1038/nbt.4314 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA HG2PE UT WOS:000454804600017 PM 30531897 DA 2020-07-01 ER PT J AU Chattopadhyay, PK Gierahn, TM Roederer, M Love, JC AF Chattopadhyay, Pratip K. Gierahn, Todd M. Roederer, Mario Love, J. Christopher TI Single-cell technologies for monitoring immune systems SO NATURE IMMUNOLOGY LA English DT Review ID NATURAL-KILLER-CELLS; FLOW-CYTOMETRY; MIGRATION BEHAVIOR; GENE-EXPRESSION; MASS CYTOMETRY; ACTIVATION; ANTIBODIES; SECRETION; HIERARCHY; RESPONSES AB The complex heterogeneity of cells, and their interconnectedness with each other, are major challenges to identifying clinically relevant measurements that reflect the state and capability of the immune system. Highly multiplexed, single-cell technologies may be critical for identifying correlates of disease or immunological interventions as well as for elucidating the underlying mechanisms of immunity. Here we review limitations of bulk measurements and explore advances in single-cell technologies that overcome these problems by expanding the depth and breadth of functional and phenotypic analysis in space and time. The geometric increases in complexity of data make formidable hurdles for exploring, analyzing and presenting results. We summarize recent approaches to making such computations tractable and discuss challenges for integrating heterogeneous data obtained using these single-cell technologies. C1 [Chattopadhyay, Pratip K.; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gierahn, Todd M.; Love, J. Christopher] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. C1 [Chattopadhyay, Pratip K.; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Gierahn, Todd M.; Love, J. Christopher] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. RP Love, JC (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM clove@mit.edu EM clove@mit.edu OI Chattopadhyay, Pratip/0000-0002-5457-9666 FU W.M. Keck FoundationW.M. Keck Foundation; US National Institute of Allergy And Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [1U19AI089992, 1R56AI104274, 5R21AI106025] FX This work was supported by the W.M. Keck Foundation and the US National Institute of Allergy And Infectious Diseases (1U19AI089992, 1R56AI104274 and 5R21AI106025). The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institute of Allergy And Infectious Diseases or the US National Institutes of Health. We thank A. Shalek for helpful comments on scRNA-seq and N. Aghaeepour for discussions about data-analysis tools. J.C.L. is a Camille Dreyfus Teacher-Scholar. We acknowledge the service to the MIT community of the late Sean Collier. 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Immunol. PD FEB PY 2014 VL 15 IS 2 BP 128 EP 135 DI 10.1038/ni.2796 PG 8 WC Immunology SC Immunology GA 295XV UT WOS:000330150600004 PM 24448570 OA Green Accepted DA 2020-07-01 ER PT J AU Romee, R Rosario, M Berrien-Elliott, MM Wagner, JA Jewell, BA Schappe, T Leong, JW Abdel-Latif, S Schneider, SE Willey, S Neal, CC Yu, LY Oh, ST Lee, YS Mulder, A Claas, F Cooper, MA Fehniger, TA AF Romee, Rizwan Rosario, Maximillian Berrien-Elliott, Melissa M. Wagner, Julia A. Jewell, Brea A. Schappe, Timothy Leong, Jeffrey W. Abdel-Latif, Sara Schneider, Stephanie E. Willey, Sarah Neal, Carly C. Yu, Liyang Oh, Stephen T. Lee, Yi-Shan Mulder, Arend Claas, Frans Cooper, Megan A. Fehniger, Todd A. TI Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID MASS CYTOMETRY; NK CELLS; TRANSPLANTATION; RECEPTOR; SURVIVAL; OUTCOMES; RELAPSE; IMMUNE; TREAT AB Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon-gamma production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML. C1 [Romee, Rizwan; Rosario, Maximillian; Berrien-Elliott, Melissa M.; Wagner, Julia A.; Jewell, Brea A.; Schappe, Timothy; Leong, Jeffrey W.; Abdel-Latif, Sara; Schneider, Stephanie E.; Willey, Sarah; Neal, Carly C.; Fehniger, Todd A.] Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO 63110 USA. [Rosario, Maximillian; Lee, Yi-Shan] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. [Yu, Liyang; Oh, Stephen T.] Washington Univ, Sch Med, Dept Med, Div Hematol, St Louis, MO 63110 USA. [Mulder, Arend; Claas, Frans] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2333 ZC Leiden, Netherlands. [Cooper, Megan A.] Washington Univ, Sch Med, Dept Pediat, Div Rheumatol, St Louis, MO 63110 USA. C1 [Romee, Rizwan; Rosario, Maximillian; Berrien-Elliott, Melissa M.; Wagner, Julia A.; Jewell, Brea A.; Schappe, Timothy; Leong, Jeffrey W.; Abdel-Latif, Sara; Schneider, Stephanie E.; Willey, Sarah; Neal, Carly C.; Fehniger, Todd A.] Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO 63110 USA. [Rosario, Maximillian; Lee, Yi-Shan] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. [Yu, Liyang; Oh, Stephen T.] Washington Univ, Sch Med, Dept Med, Div Hematol, St Louis, MO 63110 USA. [Mulder, Arend; Claas, Frans] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2333 ZC Leiden, Netherlands. [Cooper, Megan A.] Washington Univ, Sch Med, Dept Pediat, Div Rheumatol, St Louis, MO 63110 USA. RP Fehniger, TA (reprint author), Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO 63110 USA. EM tfehnige@wustl.edu EM tfehnige@wustl.edu RI Rosario, Max/P-3111-2017; rosario, maxim/O-6098-2019 FU American Society of Hematology Foundation; Conquer Cancer Foundation of the American Society of Clinical Oncology; WUSM Siteman Cancer Center Developmental Research Award and Team Science Award; WUSM Institute of Clinical and Translational Research Award; Leukemia Specialized Program of Research Excellence Development Research Award [P50 CA171963]; Howard Hughes Medical Institute Medical Fellow Award; Translational TL1 program, NIH/National Cancer Institute (NCI) [F32 CA200253]; V Foundation for Cancer Research; Gabrielle's Angel Foundation for Cancer Research; Immunomonitoring Laboratory; Center for Human Immunology and Immunotherapy Programs; Biological Therapy Core; Small Animal Cancer Imaging Core; NCI Cancer Center Support grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA91842]; [P50 CA94056] FX This work was supported by the American Society of Hematology Foundation, the Conquer Cancer Foundation of the American Society of Clinical Oncology, the WUSM Siteman Cancer Center Developmental Research Award and Team Science Award, the WUSM Institute of Clinical and Translational Research Award, the Leukemia Specialized Program of Research Excellence (P50 CA171963) Development Research Award, the Howard Hughes Medical Institute Medical Fellow Award, the Translational TL1 program, NIH/National Cancer Institute (NCI) grant F32 CA200253, the V Foundation for Cancer Research, and the Gabrielle's Angel Foundation for Cancer Research. Technical support was provided by the Immunomonitoring Laboratory (also supported by the Center for Human Immunology and Immunotherapy Programs), the Biological Therapy Core, and the Small Animal Cancer Imaging Core (also supported by P50 CA94056), which are supported by the NCI Cancer Center Support grant P30CA91842. We acknowledge the use of the Protein Production and Purification Facility for CyTOF mAb conjugation (P30 AR048335). 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Transl. Med. PD SEP 21 PY 2016 VL 8 IS 357 AR 357ra123 DI 10.1126/scitranslmed.aaf2341 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA EE2UJ UT WOS:000389440100003 PM 27655849 OA Green Accepted, Bronze DA 2020-07-01 ER PT J AU Ornatsky, O Bandura, D Baranov, V Nitz, M Winnik, MA Tanner, S AF Ornatsky, Olga Bandura, Dmitry Baranov, Vladimir Nitz, Mark Winnik, Mitchell A. Tanner, Scott TI Highly multiparametric analysis by mass cytometry SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Review DE Mass cytometry; Metal-tagged antibodies; Metal-encoded beads; Multiparametric single cell assay; Flow cytometry; Bead array ID ELEMENT-TAGGED IMMUNOASSAY; ACUTE MYELOID-LEUKEMIA; FLOW-CYTOMETRY; MULTIPLEX BIOASSAY; CELL SUBSETS; ARRAY ASSAYS; ICP-MS; BIOMARKERS; DIAGNOSIS; PANEL AB This review paper describes a new technology, mass cytometry, that addresses applications typically run by flow cytometer analyzers, but extends the capability to highly multiparametric analysis. The detection technology is based on atomic mass spectrometry. It offers quantitation, specificity and dynamic range of mass spectrometry in a format that is familiar to flow cytometry practitioners. The mass cytometer does not require compensation, allowing the application of statistical techniques: this has been impossible given the constraints of fluorescence noise with traditional cytometry instruments. Instead of "colors" the mass cytometer "reads" the stable isotope tags attached to antibodies using metal-chelating labeling reagents. Because there are many available stable isotopes, and the mass spectrometer provides exquisite resolution between detection channels, many parameters can be measured as easily as one. For example, in a single tube the technique allows for the ready detection and characterization of the major cell subsets in blood or bone marrow. Here we describe mass cytometric immunophenotyping of human leukemia cell lines and leukemia patient samples, differential cell analysis of normal peripheral and umbilical cord blood: intracellular protein identification and metal-encoded bead arrays. (C) 2010 Elsevier B.V. All rights reserved. C1 [Ornatsky, Olga; Bandura, Dmitry; Baranov, Vladimir; Nitz, Mark; Winnik, Mitchell A.; Tanner, Scott] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada. [Ornatsky, Olga; Bandura, Dmitry; Baranov, Vladimir; Tanner, Scott] DVS Sviences Inc, Richmond Hill, ON L4S 1Z5, Canada. C1 [Ornatsky, Olga; Bandura, Dmitry; Baranov, Vladimir; Nitz, Mark; Winnik, Mitchell A.; Tanner, Scott] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada. [Ornatsky, Olga; Bandura, Dmitry; Baranov, Vladimir; Tanner, Scott] DVS Sviences Inc, Richmond Hill, ON L4S 1Z5, Canada. RP Ornatsky, O (reprint author), Univ Toronto, Dept Chem, 80 St George St, Toronto, ON M5S 3H6, Canada. EM olga.ornatsky@utoronto.ca EM olga.ornatsky@utoronto.ca RI Winnik, Mitchell A/R-8621-2018 FU Genome Canada through the Ontario Genomics InstituteGenome Canada; Ontario Ministry of Research and InnovationMinistry of Research and Innovation, Ontario; National Institutes of Health [NIH]United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01-GM076127]; NSERC CanadaNatural Sciences and Engineering Research Council of Canada; DVS Sciences Inc. FX This project was funded by Genome Canada through the Ontario Genomics Institute, the Ontario Ministry of Research and Innovation, the National Institutes of Health [NIH grant R01-GM076127], NSERC Canada, and DVS Sciences Inc. Special thanks is extended to Dr. Qing Chang, Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Ontario for the Panc-1 cells, and Dr. M. Milavsky and Dr. J. Wang, University Health Network (Toronto General Research Institute) for HSC and leukemia samples, respectively. Provision of leukemia bone marrow samples by the Quebec Leukemia Cell Bank (BCLQ) is gratefully acknowledged. 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Immunol. Methods PD SEP 30 PY 2010 VL 361 IS 1-2 BP 1 EP 20 DI 10.1016/j.jim.2010.07.002 PG 20 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 676FQ UT WOS:000283896800001 PM 20655312 DA 2020-07-01 ER PT J AU Becher, B Schlitzer, A Chen, JM Mair, F Sumatoh, HR Teng, KWW Low, D Ruedl, C Riccardi-Castagnoli, P Poidinger, M Greter, M Ginhoux, F Newell, EW AF Becher, Burkhard Schlitzer, Andreas Chen, Jinmiao Mair, Florian Sumatoh, Hermi R. Teng, Karen Wei Weng Low, Donovan Ruedl, Christiane Riccardi-Castagnoli, Paola Poidinger, Michael Greter, Melanie Ginhoux, Florent Newell, Evan W. TI High-dimensional analysis of the murine myeloid cell system SO NATURE IMMUNOLOGY LA English DT Article ID CD11B(+) DENDRITIC CELLS; SUPPRESSOR-CELLS; STEADY-STATE; T-CELLS; GM-CSF; MONOCYTES; MACROPHAGES; IMMUNE; MOUSE; EXPRESSION AB Advances in cell-fate mapping have revealed the complexity in phenotype, ontogeny and tissue distribution of the mammalian myeloid system. To capture this phenotypic diversity, we developed a 38-antibody panel for mass cytometry and used dimensionality reduction with machine learning-aided cluster analysis to build a composite of murine (mouse) myeloid cells in the steady state across lymphoid and nonlymphoid tissues. In addition to identifying all previously described myeloid populations, higher-order analysis allowed objective delineation of otherwise ambiguous subsets, including monocyte-macrophage intermediates and an array of granulocyte variants. Using mice that cannot sense granulocyte macrophage-colony stimulating factor GM-CSF (Csf2rb(-/-)), which have discrete alterations in myeloid development, we confirmed differences in barrier tissue dendritic cells, lung macrophages and eosinophils. The methodology further identified variations in the monocyte and innate lymphoid cell compartment that were unexpected, which confirmed that this approach is a powerful tool for unambiguous and unbiased characterization of the myeloid system. C1 [Becher, Burkhard; Schlitzer, Andreas; Chen, Jinmiao; Sumatoh, Hermi R.; Teng, Karen Wei Weng; Low, Donovan; Riccardi-Castagnoli, Paola; Poidinger, Michael; Ginhoux, Florent; Newell, Evan W.] ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore. [Mair, Florian; Greter, Melanie] Univ Zurich, Inst Expt Immunol, CH-8091 Zurich, Switzerland. [Ruedl, Christiane] Nanyang Technol Univ, Sch Biol Sci, Singapore 639798, Singapore. C1 [Becher, Burkhard; Schlitzer, Andreas; Chen, Jinmiao; Sumatoh, Hermi R.; Teng, Karen Wei Weng; Low, Donovan; Riccardi-Castagnoli, Paola; Poidinger, Michael; Ginhoux, Florent; Newell, Evan W.] ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore. [Mair, Florian; Greter, Melanie] Univ Zurich, Inst Expt Immunol, CH-8091 Zurich, Switzerland. [Ruedl, Christiane] Nanyang Technol Univ, Sch Biol Sci, Singapore 639798, Singapore. RP Newell, EW (reprint author), Univ Zurich, Inst Expt Immunol, Sternwartstr 2, CH-8091 Zurich, Switzerland. EM becher@immunology.uzh.ch; evan_newell@immunol.a-staredu.sg EM becher@immunology.uzh.ch; evan_newell@immunol.a-staredu.sg RI Newell, Evan/AAE-9470-2020; Ruedl, christiane/A-2219-2011; Schlitzer, Andreas/R-2237-2016; Newell, Evan W/F-9711-2012 OI Newell, Evan/0000-0002-2889-243X; Ruedl, christiane/0000-0002-5599-6541; Schlitzer, Andreas/0000-0001-7662-3712; Newell, Evan W/0000-0002-2889-243X; Mair, Florian/0000-0001-6732-5449; Greter, Melanie/0000-0002-7220-5369; Poidinger, Michael/0000-0002-1047-2277; Becher, Burkhard/0000-0002-1541-7867 FU A*STAR/SIgNAgency for Science Technology & Research (ASTAR); Swiss National Science FoundationSwiss National Science Foundation (SNSF) [PP03P3_144781, 316030_150768, 310030_146130, CRSII3_136203]; European Union FP7 project TargetBraIn; University Research Priority Project 'Translational Cancer Research'; European Union FP7 project NeuroKine; European Union FP7 project Advanced T-cell Engineered for Cancer Therapy (ATECT) FX The authors thank the SIgN community, the SIgN Flow Cytometry Facility and members of E.W.N.'s, F.G.'s and B.B.'s labs, and L.G. Ng for helpful discussion. Some antibodies used for generating the mass cytometry panels were provided by R. Balderas and A. Tiong (Becton Dickinson). The antibodies generated by BioXcell were provided for this analysis free of charge. B.B. performed this work while on sabbatical at A*STAR/SIgN. Supported by A*STAR/SIgN (P.R.-C., F.G., M.P., E.W.N.) and the Swiss National Science Foundation (PP03P3_144781 (M.G.), 316030_150768, 310030_146130 and CRSII3_136203 (B.B.)), European Union FP7 project TargetBraIn, NeuroKine, Advanced T-cell Engineered for Cancer Therapy (ATECT) and the University Research Priority Project 'Translational Cancer Research' (B.B.). 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Immunol. PD DEC PY 2014 VL 15 IS 12 BP 1181 EP 1189 DI 10.1038/ni.3006 PG 9 WC Immunology SC Immunology GA AT3NR UT WOS:000344841900015 PM 25306126 DA 2020-07-01 ER PT J AU Gury-BenAri, M Thaiss, CA Serafini, N Winter, DR Giladi, A Lara-Astiaso, D Levy, M Salame, TM Weiner, A David, E Shapiro, H Dori-Bachash, M Pevsner-Fischer, M Lorenzo-Vivas, E Keren-Shaul, H Paul, F Harmelin, A Eberl, G Itzkovitz, S Tanay, A Di Santo, JP Elinav, E Amit, I AF Gury-BenAri, Meital Thaiss, Christoph A. Serafini, Nicolas Winter, Deborah R. Giladi, Amir Lara-Astiaso, David Levy, Maayan Salame, Tomer Meir Weiner, Assaf David, Eyal Shapiro, Hagit Dori-Bachash, Mally Pevsner-Fischer, Meirav Lorenzo-Vivas, Erika Keren-Shaul, Hadas Paul, Franziska Harmelin, Alon Eberl, Gerard Itzkovitz, Shalev Tanay, Amos Di Santo, James P. Elinav, Eran Amit, Ido TI The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome SO CELL LA English DT Article ID TRANSCRIPTION FACTOR GATA3; ROR-GAMMA-T; RNA-SEQ; FUNCTIONAL PLASTICITY; COMMENSAL MICROFLORA; NKP46(+) CELLS; INFLAMMATION; HOMEOSTASIS; FATE; DIFFERENTIATION AB Innate lymphoid cells (ILCs) are critical modulators of mucosal immunity, inflammation, and tissue homeostasis, but their full spectrum of cellular states and regulatory landscapes remains elusive. Here, we combine genome-wide RNA-seq, ChIP-seq, and ATAC-seq to compare the transcriptional and epigenetic identity of small intestinal ILCs, identifying thousands of distinct gene profiles and regulatory elements. Single-cell RNA-seq and flow and mass cytometry analyses reveal compartmentalization of cytokine expression and metabolic activity within the three classical ILC subtypes and highlight transcriptional states beyond the current canonical classification. In addition, using antibiotic intervention and germ-free mice, we characterize the effect of the microbiome on the ILC regulatory landscape and determine the response of ILCs to microbial colonization at the single-cell level. Together, our work characterizes the spectrum of transcriptional identities of small intestinal ILCs and describes how ILCs differentially integrate signals from the microbial microenvironment to generate phenotypic and functional plasticity. C1 [Gury-BenAri, Meital; Thaiss, Christoph A.; Winter, Deborah R.; Giladi, Amir; Lara-Astiaso, David; Levy, Maayan; Weiner, Assaf; David, Eyal; Shapiro, Hagit; Dori-Bachash, Mally; Pevsner-Fischer, Meirav; Lorenzo-Vivas, Erika; Keren-Shaul, Hadas; Paul, Franziska; Elinav, Eran; Amit, Ido] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. [Serafini, Nicolas; Di Santo, James P.] Inst Pasteur, Innate Immun Unit, F-75015 Paris, France. [Serafini, Nicolas; Di Santo, James P.] INSERM, U1223, Paris, France. [Salame, Tomer Meir] Weizmann Inst Sci, Biol Serv Unit, IL-76100 Rehovot, Israel. [Harmelin, Alon] Weizmann Inst Sci, Dept Vet Resources, IL-76100 Rehovot, Israel. [Eberl, Gerard] Inst Pasteur, Dept Immunol, F-75015 Paris, France. [Eberl, Gerard] CNRS, URA 1961, F-75015 Paris, France. [Itzkovitz, Shalev] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Tanay, Amos] Weizmann Inst Sci, Dept Comp Sci & Appl Math, IL-76100 Rehovot, Israel. [Tanay, Amos] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel. C1 [Gury-BenAri, Meital; Thaiss, Christoph A.; Winter, Deborah R.; Giladi, Amir; Lara-Astiaso, David; Levy, Maayan; Weiner, Assaf; David, Eyal; Shapiro, Hagit; Dori-Bachash, Mally; Pevsner-Fischer, Meirav; Lorenzo-Vivas, Erika; Keren-Shaul, Hadas; Paul, Franziska; Elinav, Eran; Amit, Ido] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. [Serafini, Nicolas; Di Santo, James P.] Inst Pasteur, Innate Immun Unit, F-75015 Paris, France. [Serafini, Nicolas; Di Santo, James P.] INSERM, U1223, Paris, France. [Salame, Tomer Meir] Weizmann Inst Sci, Biol Serv Unit, IL-76100 Rehovot, Israel. [Harmelin, Alon] Weizmann Inst Sci, Dept Vet Resources, IL-76100 Rehovot, Israel. [Eberl, Gerard] Inst Pasteur, Dept Immunol, F-75015 Paris, France. [Eberl, Gerard] CNRS, URA 1961, F-75015 Paris, France. [Itzkovitz, Shalev] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. [Tanay, Amos] Weizmann Inst Sci, Dept Comp Sci & Appl Math, IL-76100 Rehovot, Israel. [Tanay, Amos] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel. RP Elinav, E; Amit, I (reprint author), Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. EM eran.elinav@weizmann.ac.il; ido.amit@weizmann.ac.il EM eran.elinav@weizmann.ac.il; ido.amit@weizmann.ac.il RI Di Santo, James/N-3143-2019; Di Santo, James P/M-4298-2014; SERAFINI, nicolas/S-5675-2019; Eberl, Gerard/A-1160-2013 OI Di Santo, James/0000-0002-7146-1862; Di Santo, James P/0000-0002-7146-1862; SERAFINI, nicolas/0000-0002-7440-4353; Eberl, Gerard/0000-0002-1119-5638; Lorenzo Vivas, Erika/0000-0002-8150-5902; Winter, Deborah/0000-0003-1806-673X; Paul, Franziska/0000-0003-0344-6764; Elinav, Eran/0000-0002-5775-2110 FU Boehringer Ingelheim Fonds PhD FellowshipBoehringer Ingelheim; Abisch Frenkel Foundation for the Promotion of Life Sciences; Gurwin Family Fund for Scientific Research; Leona M. and Harry B. Helmsley Charitable Trust; Crown Endowment Fund for Immunological Research; estate of J. Gitlitz; estate of L. Hershkovich; Benoziyo Endowment Fund for the Advancement of Science; Adelis Foundation; French National Center for Scientific Research (CNRS)Centre National de la Recherche Scientifique (CNRS); European Research CouncilEuropean Research Council (ERC); Marie Curie Integration grant; German-Israeli Foundation for Scientific Research and DevelopmentGerman-Israeli Foundation for Scientific Research and Development; Israel Science FoundationIsrael Science Foundation; Minerva Foundation; Rising Tide Foundation; Helmholtz FoundationHelmholtz Association; European Foundation for the Study of Diabetes; European Research CouncilEuropean Research Council (ERC) [309788]; Israel Science foundationIsrael Science Foundation [782/11]; BLUEPRINT FP7 consortium; Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine; Minerva Stiftung research grant; National Human Genome Research Institute Center for Excellence in Genome Science [1P50HG006193]; Israeli Ministry of Science, Technology and Space; David and Fela Shapell Family Foundation; Abramson Family Center for Young Scientists FX We thank the members of I.A.'s and E.E.'s labs for fruitful discussions, Carmit Bar-Nathan for GF mouse care taking, Elena Kartvelishvily for help with electron microscopy, Melanie Flach for technical advice, and Maayan Wigelmann for art work. C.A.T. received a Boehringer Ingelheim Fonds PhD Fellowship. E.E. is supported by Y. and R. Ungar; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Crown Endowment Fund for Immunological Research; the estate of J. Gitlitz; the estate of L. Hershkovich; the Benoziyo Endowment Fund for the Advancement of Science; the Adelis Foundation; J.L. and V. Schwartz; A. and G. Markovitz; A. and C. Adelson; the French National Center for Scientific Research (CNRS); D.L. Schwarz; the V.R. Schwartz Research Fellow Chair; L. Steinberg; J.N. Halpern; A. Edelheit, and by grants funded by the European Research Council; a Marie Curie Integration grant; the German-Israeli Foundation for Scientific Research and Development; the Israel Science Foundation; the Minerva Foundation; the Rising Tide Foundation; the Helmholtz Foundation; and the European Foundation for the Study of Diabetes. E.E. is the incumbent of the Rina Gudinski Career Development Chair and a senior fellow of the Canadian Institute For Advanced Research (CIFAR). I. A. is supported by the European Research Council (309788), the I-CORE for chromatin and RNA regulation, and personal grants from the Israel Science foundation (782/11) and the BLUEPRINT FP7 consortium, the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, a Minerva Stiftung research grant, the National Human Genome Research Institute Center for Excellence in Genome Science (1P50HG006193), the Israeli Ministry of Science, Technology and Space, the David and Fela Shapell Family Foundation, and the Abramson Family Center for Young Scientists. I.A. is the incumbent of the Alan and Laraine Fischer Career Development Chair. 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Yu, Wen-Hsuan Du, Yi Lee, Heng-Huan Li, Chia-Wei Chou, Chao-Kai Lim, Seung-Oe Chang, Shih-Shin Litton, Jennifer Arun, Banu Hortobagyi, Gabriel N. Hung, Mien-Chie TI PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; OVARIAN-CANCER; BREAST-CANCER; CHEMOTHERAPY; THERAPY; OVEREXPRESSION; PEMBROLIZUMAB; COMBINATION; ACTIVATION; PROVIDES AB Purpose: To explore whether a cross-talk exists between PARP inhibition and PD-L1/PD-1 immune checkpoint axis, and determine whether blockade of PD-L1/PD-1 potentiates PARP inhibitor (PARPi) in tumor suppression. Experimental Design: Breast cancer cell lines, xenograft tumors, and syngeneic tumors treated with PARPi were assessed for PD-L1 expression by immunoblotting, IHC, and FACS analyses. The phospho-kinase antibody array screen was used to explore the underlying mechanism of PARPi-induced PD-L1 upregulation. The therapeutic efficacy of PARPi alone, PD-L1 blockade alone, or their combination was tested in a syngeneic tumor model. The tumor-infiltrating lymphocytes and tumor cells isolated from syngeneic tumors were analyzed by CyTOF and FACS to evaluate the activity of antitumor immunity in the tumor microenvironment. Results: PARPi upregulated PD-L1 expression in breast cancer cell lines and animal models. Mechanistically, PARPi inactivated GSK3b, which in turn enhanced PARPi-mediated PD-L1 upregulation. PARPi attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 resensitized PARPi-treated cancer cells to T-cell killing. The combination of PARPi and anti-PD-L1 therapy compared with each agent alone significantly increased the therapeutic efficacy in vivo. Conclusions: Our study demonstrates a cross-talk between PARPi and tumor-associated immunosuppression and provides evidence to support the combination of PARPi and PD-L1 or PD-1 immune checkpoint blockade as a potential therapeutic approach to treat breast cancer. (C) 2017 AACR. C1 [Jiao, Shiping; Xia, Weiya; Yamaguchi, Hirohito; Wei, Yongkun; Chen, Mei-Kuang; Hsu, Jung-Mao; Hsu, Jennifer L.; Yu, Wen-Hsuan; Du, Yi; Lee, Heng-Huan; Li, Chia-Wei; Chou, Chao-Kai; Lim, Seung-Oe; Chang, Shih-Shin; Hung, Mien-Chie] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, 1515 Holcombe Blvd,Unit 108, Houston, TX 77030 USA. [Jiao, Shiping; Chen, Mei-Kuang; Yu, Wen-Hsuan; Hung, Mien-Chie] Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX USA. [Hsu, Jennifer L.; Hung, Mien-Chie] China Med Univ, Grad Inst Biomed Sci, Taichung, Taiwan. [Hsu, Jennifer L.; Hung, Mien-Chie] China Med Univ, Ctr Mol Med, Taichung, Taiwan. [Hsu, Jennifer L.; Hung, Mien-Chie] Asia Univ, Dept Biotechnol, Taichung, Taiwan. [Litton, Jennifer; Arun, Banu; Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. C1 [Jiao, Shiping; Xia, Weiya; Yamaguchi, Hirohito; Wei, Yongkun; Chen, Mei-Kuang; Hsu, Jung-Mao; Hsu, Jennifer L.; Yu, Wen-Hsuan; Du, Yi; Lee, Heng-Huan; Li, Chia-Wei; Chou, Chao-Kai; Lim, Seung-Oe; Chang, Shih-Shin; Hung, Mien-Chie] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, 1515 Holcombe Blvd,Unit 108, Houston, TX 77030 USA. [Jiao, Shiping; Chen, Mei-Kuang; Yu, Wen-Hsuan; Hung, Mien-Chie] Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX USA. [Hsu, Jennifer L.; Hung, Mien-Chie] China Med Univ, Grad Inst Biomed Sci, Taichung, Taiwan. [Hsu, Jennifer L.; Hung, Mien-Chie] China Med Univ, Ctr Mol Med, Taichung, Taiwan. [Hsu, Jennifer L.; Hung, Mien-Chie] Asia Univ, Dept Biotechnol, Taichung, Taiwan. [Litton, Jennifer; Arun, Banu; Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. RP Hung, MC (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, 1515 Holcombe Blvd,Unit 108, Houston, TX 77030 USA. EM mhung@mdanderson.org EM mhung@mdanderson.org RI Lim, Seung-Oe/D-3703-2011; Li, Chia-Wei/AAC-8660-2019; Hsu, Jung-Mao/AAC-9527-2019; Hsu, Jung-Mao/AAP-8045-2020; CHEN, MEI-KUANG/V-9284-2017 OI Li, Chia-Wei/0000-0002-2531-2866; CHEN, MEI-KUANG/0000-0001-8027-8990; Jiao, Shiping/0000-0001-6546-9369; Du, Yi/0000-0002-3969-2652; CHOU, CHAO-KAI/0000-0001-5231-5264 FU NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CCSG CA016672]; Cancer Prevention & Research Institutes of Texas [DP150052, RP160710]; Breast Cancer Research Foundation; Patel Memorial Breast Cancer Endowment Fund; National Breast Cancer Foundation, Inc.; University of Texas MD Anderson Cancer Center-China Medical University and Hospital Sister Institution Fund; Ministry of Science and TechnologyMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT); International Research-intensive Centers of Excellence in Taiwan (I-RiCE) [MOST 105-2911-I-002-302]; Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence [MOHW106-TDU-B-212-144003] FX This work was partially supported by the following: the NIH (CCSG CA016672), Cancer Prevention & Research Institutes of Texas (DP150052 and RP160710), Breast Cancer Research Foundation grant (to M.-C. Hung and G. N. Hortobagyi), Patel Memorial Breast Cancer Endowment Fund, National Breast Cancer Foundation, Inc., The University of Texas MD Anderson Cancer Center-China Medical University and Hospital Sister Institution Fund (to M.-C. Hung), Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE; MOST 105-2911-I-002-302), and Ministry of Health and Welfare, China Medical University Hospital Cancer Research Center of Excellence (MOHW106-TDU-B-212-144003). 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[Wagner, Allon; Yosef, Nir] Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA USA. [Regev, Aviv] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA USA. [Regev, Aviv] Broad Inst MIT & Harvard, Cambridge, MA USA. [Yosef, Nir] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Yosef, Nir] Harvard Univ, Boston, MA 02115 USA. C1 [Wagner, Allon; Yosef, Nir] Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA. [Wagner, Allon; Yosef, Nir] Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA USA. [Regev, Aviv] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA USA. [Regev, Aviv] Broad Inst MIT & Harvard, Cambridge, MA USA. [Yosef, Nir] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Yosef, Nir] Harvard Univ, Boston, MA 02115 USA. RP Regev, A (reprint author), MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA USA.; Regev, A (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA. EM aregev@broadinstitute.org EM aregev@broadinstitute.org RI t, lf/AAJ-4924-2020 OI Wagner, Allon/0000-0001-5095-6009 FU US National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [U01 MH105979]; Klarman Cell Observatory at the Broad Institute, NIH [P50 HG006193]; National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30-CA14051]; NIH BRAIN grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1U01MH105960-01]; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [1U24CA180922]; NIAIDUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [1U24AI118672-01] FX We thank E. Lander, A.K. Shalek, R.B. Fletcher, O. Ram, and D. Stafford for helpful discussions, and L. Gaffney and A. Hupalowska for artwork. A.W. and N.Y. were supported in part by the BRAIN Initiative grant U01 MH105979 from the US National Institute of Mental Health. A.R. is an Investigator of the Howard Hughes Medical Institute and was supported by the Klarman Cell Observatory at the Broad Institute, NIH grant P50 HG006193, Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, NIH BRAIN grant 1U01MH105960-01, NCI grant 1U24CA180922, and NIAID grant 1U24AI118672-01. 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Biotechnol. PD NOV PY 2016 VL 34 IS 11 BP 1145 EP 1160 DI 10.1038/nbt.3711 PG 16 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EB6PG UT WOS:000387506500027 PM 27824854 OA Green Accepted DA 2020-07-01 ER PT J AU Van Gassen, S Callebaut, B Van Helden, MJ Lambrecht, BN Demeester, P Dhaene, T Saeys, Y AF Van Gassen, Sofie Callebaut, Britt Van Helden, Mary J. Lambrecht, Bart N. Demeester, Piet Dhaene, Tom Saeys, Yvan TI FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data SO CYTOMETRY PART A LA English DT Article DE polychromatic flow cytometry; mass cytometry; exploratory data analysis; visualization method; self-organizing map; bioinformatics ID IDENTIFICATION; ALGORITHM AB The number of markers measured in both flow and mass cytometry keeps increasing steadily. Although this provides a wealth of information, it becomes infeasible to analyze these datasets manually. When using 2D scatter plots, the number of possible plots increases exponentially with the number of markers and therefore, relevant information that is present in the data might be missed. In this article, we introduce a new visualization technique, called FlowSOM, which analyzes Flow or mass cytometry data using a Self-Organizing Map. Using a two-level clustering and star charts, our algorithm helps to obtain a clear overview of how all markers are behaving on all cells, and to detect subsets that might be missed otherwise. R code is available at and will be made available at Bioconductor. (c) 2015 International Society for Advancement of Cytometry C1 [Van Gassen, Sofie; Callebaut, Britt; Demeester, Piet; Dhaene, Tom] Univ Ghent, Dept Informat Technol, IMinds, B-9000 Ghent, Belgium. [Van Gassen, Sofie; Van Helden, Mary J.; Lambrecht, Bart N.; Saeys, Yvan] VIB, Inflammat Res Ctr, Ghent, Belgium. [Van Gassen, Sofie; Van Helden, Mary J.; Lambrecht, Bart N.; Saeys, Yvan] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium. C1 [Van Gassen, Sofie; Callebaut, Britt; Demeester, Piet; Dhaene, Tom] Univ Ghent, Dept Informat Technol, IMinds, B-9000 Ghent, Belgium. [Van Gassen, Sofie; Van Helden, Mary J.; Lambrecht, Bart N.; Saeys, Yvan] VIB, Inflammat Res Ctr, Ghent, Belgium. [Van Gassen, Sofie; Van Helden, Mary J.; Lambrecht, Bart N.; Saeys, Yvan] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium. RP Van Gassen, S (reprint author), Univ Ghent VIB, Technol Pk 927, B-9052 Ghent, Zwijnaarde, Belgium. EM sofie.vangassen@irc.vib-ugent.be EM sofie.vangassen@irc.vib-ugent.be RI Lambrecht, Bart N/K-2484-2014; Saeys, Yvan/C-1311-2009 OI Lambrecht, Bart N/0000-0003-4376-6834; Saeys, Yvan/0000-0002-0415-1506; Van Gassen, Sofie/0000-0002-7119-5330 FU Agency for Innovation by Science and Technology (IWT)Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT); Ghent University Multidisciplinary Research Partnership Bioinformatics FX Grant sponsors: Agency for Innovation by Science and Technology (IWT); Ghent University Multidisciplinary Research Partnership Bioinformatics CR Aghaeepour N, 2013, NAT METHODS, V10, P228, DOI [10.1038/NMETH.2365, 10.1038/nmeth.2365] Aghaeepour N, 2011, CYTOM PART A, V79A, P6, DOI 10.1002/cyto.a.21007 Amir ED, 2013, NAT BIOTECHNOL, V31, P545, DOI 10.1038/nbt.2594 Bendall SC, 2011, SCIENCE, V332, P687, DOI 10.1126/science.1198704 Cron A, 2013, PLOS COMPUT BIOL, V9, DOI 10.1371/journal.pcbi.1003130 Csardi G, 2006, INT J COMPLEX SYST, V1695, P1, DOI DOI 10.3724/SP.J.1087.2009.02191 Finak Greg, 2009, Advances in Bioinformatics, V2009, P247646, DOI 10.1155/2009/247646 KAMADA T, 1989, INFORM PROCESS LETT, V31, P7, DOI 10.1016/0020-0190(89)90102-6 KOHONEN T, 1990, P IEEE, V78, P1464, DOI 10.1109/5.58325 Lo K, 2008, CYTOM PART A, V73A, P321, DOI 10.1002/cyto.a.20531 Lo K, 2009, BMC BIOINFORMATICS, V10, DOI 10.1186/1471-2105-10-145 Naim I, 2014, CYTOM PART A, V85, P408, DOI 10.1002/cyto.a.22446 Pyne S, 2014, PLOS ONE, V9, DOI 10.1371/journal.pone.0100334 Pyne S, 2009, P NATL ACAD SCI USA, V106, P8519, DOI 10.1073/pnas.0903028106 Qiu P, 2011, NAT BIOTECHNOL, V29, P886, DOI 10.1038/nbt.1991 Wehrens R, 2007, J STAT SOFTW, V21, P1 WHITNEY VKM, 1972, COMMUN ACM, V15, P273, DOI 10.1145/361284.361299 Wilkerson M, 2013, CONSENSUSCLUSTERPLUS NR 18 TC 180 Z9 180 U1 5 U2 25 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD JUL PY 2015 VL 87A IS 7 SI SI BP 636 EP 645 DI 10.1002/cyto.a.22625 PG 10 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CL3ZK UT WOS:000356891200006 PM 25573116 DA 2020-07-01 ER PT J AU See, P Dutertre, CA Chen, JM Gunther, P McGovern, N Irac, SE Gunawan, M Beyer, M Handler, K Duan, K Bin Sumatoh, HR Ruffin, N Jouve, M Gea-Mallorqui, E Hennekam, RCM Lim, T Yip, CC Wen, M Malleret, B Low, I Shadan, NB Fen, CFS Tay, A Lum, J Zolezzi, F Larbi, A Poidinger, M Chan, JKY Chen, QF Renia, L Haniffa, M Benaroch, P Schlitzer, A Schultze, JL Newell, EW Ginhoux, F AF See, Peter Dutertre, Charles-Antoine Chen, Jinmiao Gunther, Patrick McGovern, Naomi Irac, Sergio Erdal Gunawan, Merry Beyer, Marc Handler, Kristian Duan, Kaibo Bin Sumatoh, Hermi Rizal Ruffin, Nicolas Jouve, Mabel Gea-Mallorqui, Ester Hennekam, Raoul C. M. Lim, Tony Yip, Chan Chung Wen, Ming Malleret, Benoit Low, Ivy Shadan, Nurhidaya Binte Fen, Charlene Foong Shu Tay, Alicia Lum, Josephine Zolezzi, Francesca Larbi, Anis Poidinger, Michael Chan, Jerry K. Y. Chen, Qingfeng Renia, Laurent Haniffa, Muzlifah Benaroch, Philippe Schlitzer, Andreas Schultze, Joachim L. Newell, Evan W. Ginhoux, Florent TI Mapping the human DC lineage through the integration of high-dimensional techniques SO SCIENCE LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; INTERFERON-PRODUCING CELLS; INFLUENZA-VIRUS; T-CELLS; RNA-SEQ; EXPRESSION; PROGENITOR; SUBSETS; TRAJECTORIES; MACROPHAGES AB Dendritic cells (DC) are professional antigen-presenting cells that orchestrate immune responses. The human DC population comprises two main functionally specialized lineages, whose origins and differentiation pathways remain incompletely defined. Here, we combine two high-dimensional technologies-single-cell messenger RNA sequencing (scmRNAseq) and cytometry by time-of-flight (CyTOF)-to identify human blood CD123(+)CD33(+)CD45RA(+)DC precursors (pre-DC). Pre-DC share surface markers with plasmacytoid DC (pDC) but have distinct functional properties that were previously attributed to pDC. Tracing the differentiation of DC from the bone marrow to the peripheral blood revealed that the pre-DC compartment contains distinct lineage-committed subpopulations, including one early uncommitted CD123(high) pre-DC subset and two CD45RA(+)CD123(low) lineage-committed subsets exhibiting functional differences. The discovery of multiple committed pre-DC populations opens promising new avenues for the therapeutic exploitation of DC subset-specific targeting. C1 [See, Peter; Dutertre, Charles-Antoine; Chen, Jinmiao; McGovern, Naomi; Duan, Kaibo; Bin Sumatoh, Hermi Rizal; Malleret, Benoit; Low, Ivy; Shadan, Nurhidaya Binte; Tay, Alicia; Lum, Josephine; Zolezzi, Francesca; Larbi, Anis; Poidinger, Michael; Chan, Jerry K. Y.; Renia, Laurent; Schlitzer, Andreas; Newell, Evan W.; Ginhoux, Florent] ASTAR, Singapore Immunol Network SIgN, 8A Biomed Grove,Immunos Bldg,Level 4, Singapore 138648, Singapore. [Dutertre, Charles-Antoine; Irac, Sergio Erdal; Wen, Ming] Duke NUS Med Sch, Program Emerging Infect Dis, 8 Coll Rd, Singapore 169857, Singapore. [Gunther, Patrick; Beyer, Marc; Handler, Kristian; Schultze, Joachim L.] Univ Bonn, Life & Med Sci LIMES Inst, Genom & Immunoregulat, D-32115 Bonn, Germany. [Gunawan, Merry; Haniffa, Muzlifah] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Beyer, Marc; Schultze, Joachim L.] German Ctr Neurodegenerat Dis, Platform Single Cell Genom & Epigen, D-53175 Bonn, Germany. [Beyer, Marc; Schultze, Joachim L.] Univ Bonn, D-53175 Bonn, Germany. [Ruffin, Nicolas; Jouve, Mabel; Gea-Mallorqui, Ester; Benaroch, Philippe] PSL Res Univ, INSERM, U932, Inst Curie, F-75005 Paris, France. [Hennekam, Raoul C. M.] Univ Amsterdam, Acad Med Ctr, Dept Pediat, Amsterdam, Netherlands. [Lim, Tony] Singapore Gen Hosp, Dept Anat Pathol, Singapore, Singapore. [Yip, Chan Chung] Singapore Gen Hosp, Dept Hlth Promot Board HPB & Transplant Surg, Singapore, Singapore. [Malleret, Benoit] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Microbiol & Immunol, Singapore, Singapore. [Fen, Charlene Foong Shu] Singapore Hlth Serv Flow Cytometry Core Platform, 20 Coll Rd,Discovery Tower Level 10, Singapore 169856, Singapore. [Chan, Jerry K. Y.] KK Womens & Childrens Hosp, Div Obstet & Gynaecol, Dept Reprod Med, Singapore, Singapore. [Chan, Jerry K. Y.] Duke NUS Grad Med Sch, Canc & Stem Cell Biol Program, Singapore, Singapore. [Chan, Jerry K. Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Expt Fetal Med Grp, Singapore, Singapore. [Chen, Qingfeng] ASTAR, Humanized Mouse Unit, Inst Mol & Cell Biol, Singapore, Singapore. [Chen, Qingfeng] Univ Bonn, Myeloid Cell Biol Life & Med Sci LIMES Inst, D-53115 Bonn, Germany. C1 [See, Peter; Dutertre, Charles-Antoine; Chen, Jinmiao; McGovern, Naomi; Duan, Kaibo; Bin Sumatoh, Hermi Rizal; Malleret, Benoit; Low, Ivy; Shadan, Nurhidaya Binte; Tay, Alicia; Lum, Josephine; Zolezzi, Francesca; Larbi, Anis; Poidinger, Michael; Chan, Jerry K. Y.; Renia, Laurent; Schlitzer, Andreas; Newell, Evan W.; Ginhoux, Florent] ASTAR, Singapore Immunol Network SIgN, 8A Biomed Grove,Immunos Bldg,Level 4, Singapore 138648, Singapore. [Dutertre, Charles-Antoine; Irac, Sergio Erdal; Wen, Ming] Duke NUS Med Sch, Program Emerging Infect Dis, 8 Coll Rd, Singapore 169857, Singapore. [Gunther, Patrick; Beyer, Marc; Handler, Kristian; Schultze, Joachim L.] Univ Bonn, Life & Med Sci LIMES Inst, Genom & Immunoregulat, D-32115 Bonn, Germany. [Gunawan, Merry; Haniffa, Muzlifah] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Beyer, Marc; Schultze, Joachim L.] German Ctr Neurodegenerat Dis, Platform Single Cell Genom & Epigen, D-53175 Bonn, Germany. [Beyer, Marc; Schultze, Joachim L.] Univ Bonn, D-53175 Bonn, Germany. [Ruffin, Nicolas; Jouve, Mabel; Gea-Mallorqui, Ester; Benaroch, Philippe] PSL Res Univ, INSERM, U932, Inst Curie, F-75005 Paris, France. [Hennekam, Raoul C. M.] Univ Amsterdam, Acad Med Ctr, Dept Pediat, Amsterdam, Netherlands. [Lim, Tony] Singapore Gen Hosp, Dept Anat Pathol, Singapore, Singapore. [Yip, Chan Chung] Singapore Gen Hosp, Dept Hlth Promot Board HPB & Transplant Surg, Singapore, Singapore. [Malleret, Benoit] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Microbiol & Immunol, Singapore, Singapore. [Fen, Charlene Foong Shu] Singapore Hlth Serv Flow Cytometry Core Platform, 20 Coll Rd,Discovery Tower Level 10, Singapore 169856, Singapore. [Chan, Jerry K. Y.] KK Womens & Childrens Hosp, Div Obstet & Gynaecol, Dept Reprod Med, Singapore, Singapore. [Chan, Jerry K. Y.] Duke NUS Grad Med Sch, Canc & Stem Cell Biol Program, Singapore, Singapore. [Chan, Jerry K. Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Expt Fetal Med Grp, Singapore, Singapore. [Chen, Qingfeng] ASTAR, Humanized Mouse Unit, Inst Mol & Cell Biol, Singapore, Singapore. [Chen, Qingfeng] Univ Bonn, Myeloid Cell Biol Life & Med Sci LIMES Inst, D-53115 Bonn, Germany. RP Ginhoux, F (reprint author), ASTAR, Singapore Immunol Network SIgN, 8A Biomed Grove,Immunos Bldg,Level 4, Singapore 138648, Singapore. EM florent_ginhoux@immunol.a-star.edu.sg EM florent_ginhoux@immunol.a-star.edu.sg RI Malleret, Benoit/E-9159-2011; Schlitzer, Andreas/R-2237-2016; Irac, Sergio Erdal/G-6690-2014; Malleret, Benoit/AAK-4048-2020; Newell, Evan/AAE-9470-2020 OI Malleret, Benoit/0000-0001-9658-7528; Schlitzer, Andreas/0000-0001-7662-3712; Irac, Sergio Erdal/0000-0001-5622-1409; Malleret, Benoit/0000-0001-9658-7528; Newell, Evan/0000-0002-2889-243X; Beyer, Marc/0000-0001-9704-148X; Ruffin, Nicolas/0000-0002-3698-5505; Gunther, Patrick/0000-0002-9135-7819; McGovern, Naomi/0000-0001-5200-2698; Benaroch, Philippe/0000-0002-2655-0129; chen, jinmiao/0000-0001-7547-6423; Poidinger, Michael/0000-0002-1047-2277; Gea-Mallorqui, Ester/0000-0002-6915-074X; Dutertre, Charles-Antoine/0000-0001-7950-3652 FU Singapore Immunology Network core funding; Agency for Science, Technology and Research (A*STAR), SingaporeAgency for Science Technology & Research (ASTAR); A*STAR Graduate ScholarshipAgency for Science Technology & Research (ASTAR); Wellcome TrustWellcome Trust [WT 107931/Z/15/Z]; National Research Foundation SingaporeSingapore National Research Foundation [NMRC/BNIG/2026/2014]; French National Research AgencyFrench National Research Agency (ANR) [ANR-10-INSB-04, ANR-10-IDEX-0001-02 PSL, ANR-11-LABX-0043]; Agence Nationale de Recherche contre le SIDA et les hepatites virales (ANRS)ANRSFrench National Research Agency (ANR); Emmy-Noether fellowship of the German Research Foundation [SCHL 2116/1-1]; Biomedical Research Council SingaporeAgency for Science Technology & Research (ASTAR); [Sonderforschungsbereich 645]; [704] FX We thank L. Robinson of Insight Editing London for critical review and editing of the manuscript; P. Y. J. Ai from the SingHealth Flow Cytometry Core Platform; and M. L. Ng, S. H. Tan, and T. B. Lu from the Electron Microscope Unit of NUS for their assistance. This work was supported by Singapore Immunology Network core funding (F.G. and E.W.N.); Agency for Science, Technology and Research (A*STAR), Singapore; the A*STAR Graduate Scholarship (P. S.); the Wellcome Trust (WT 107931/Z/15/Z) (M. H.); and the National Research Foundation Singapore under its cooperative basic research grant new investigator grant (NMRC/BNIG/2026/2014) and administered by the Singapore Ministry of Health's National Medical Research Council (C.-A.D). This work was supported by the French National Research Agency through the "Investments for the Future" program (France-BioImaging, ANR-10-INSB-04), LABEX DCBIOL (ANR-10-IDEX-0001-02 PSL and ANR-11-LABX-0043), and grants from Agence Nationale de Recherche contre le SIDA et les hepatites virales (ANRS) (P.B., N.R., M.J., and E.G.-M.). J. L. S., M. B., and A. S. are members of the Excellence Cluster ImmunoSensation. J. L. S. is funded by Sonderforschungsbereich 645 and 704. A.S. is funded by an Emmy-Noether fellowship (SCHL 2116/1-1) of the German Research Foundation and a Young Investigator Award of the Biomedical Research Council Singapore. F.G. and P.S. are inventors on patent application 10201607246S held by A*STAR, which covers the methods for the identification, targeting, and isolation of human dendritic cell (DC) precursors ("preDC") and their use as biomarkers of inflammatory diseases. The MARS-seq, microfluidic scmRNAseq, and microarray data sets are deposited in the Gene Expression Omnibus under accession numbers GSE98052, GSE98011, and GSE80171, respectively. 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Weber, Lukas M. Dummer, Reinhard Robinson, Mark D. Levesque, Mitchell P. Becher, Burkhard TI High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy SO NATURE MEDICINE LA English DT Article ID DIFFERENTIAL EXPRESSION ANALYSIS; MASS CYTOMETRY; LUNG-CANCER; CLINICAL ACTIVITY; PERIPHERAL-BLOOD; PD-1 BLOCKADE; T-CELLS; MELANOMA; NIVOLUMAB; SAFETY AB Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14(+)CD16-HLA-DRhi monocytes. We confirmed this by conventional flow cytometry in an independent, blinded validation cohort, and we propose that the frequency of monocytes in PBMCs may serve in clinical decision support. C1 [Krieg, Carsten; Hartmann, Felix J.; Becher, Burkhard] Univ Zurich, Inst Expt Immunol, Zurich, Switzerland. [Nowicka, Malgorzata; Weber, Lukas M.; Robinson, Mark D.] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. [Nowicka, Malgorzata; Weber, Lukas M.; Robinson, Mark D.] Univ Zurich, SIB, Zurich, Switzerland. [Guglietta, Silvia] European Inst Oncol, Dept Expt Oncol, Milan, Italy. [Schindler, Sabrina; Dummer, Reinhard; Levesque, Mitchell P.] Univ Hosp Zurich, Dept Dermatol, Zurich, Switzerland. [Krieg, Carsten] Med Univ South Carolina, Dept Microbiol & Immunol, Hollings Canc Ctr, Charleston, SC 29425 USA. [Krieg, Carsten] Med Univ South Carolina, Dept Dermatol, Hollings Canc Ctr, Charleston, SC 29425 USA. C1 [Krieg, Carsten; Hartmann, Felix J.; Becher, Burkhard] Univ Zurich, Inst Expt Immunol, Zurich, Switzerland. [Nowicka, Malgorzata; Weber, Lukas M.; Robinson, Mark D.] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. [Nowicka, Malgorzata; Weber, Lukas M.; Robinson, Mark D.] Univ Zurich, SIB, Zurich, Switzerland. [Guglietta, Silvia] European Inst Oncol, Dept Expt Oncol, Milan, Italy. [Schindler, Sabrina; Dummer, Reinhard; Levesque, Mitchell P.] Univ Hosp Zurich, Dept Dermatol, Zurich, Switzerland. [Krieg, Carsten] Med Univ South Carolina, Dept Microbiol & Immunol, Hollings Canc Ctr, Charleston, SC 29425 USA. [Krieg, Carsten] Med Univ South Carolina, Dept Dermatol, Hollings Canc Ctr, Charleston, SC 29425 USA. RP Krieg, C; Becher, B (reprint author), Univ Zurich, Inst Expt Immunol, Zurich, Switzerland.; Levesque, MP (reprint author), Univ Hosp Zurich, Dept Dermatol, Zurich, Switzerland.; Krieg, C (reprint author), Med Univ South Carolina, Dept Microbiol & Immunol, Hollings Canc Ctr, Charleston, SC 29425 USA.; Krieg, C (reprint author), Med Univ South Carolina, Dept Dermatol, Hollings Canc Ctr, Charleston, SC 29425 USA. EM kriegc@musc.edu; mitchell.levesque@usz.ch; becher@immunology.uzh.ch EM kriegc@musc.edu; mitchell.levesque@usz.ch; becher@immunology.uzh.ch RI Robinson, Mark/O-2254-2019 OI Robinson, Mark/0000-0002-3048-5518; Hogan (Schindler), Sabrina/0000-0003-3994-8109; Becher, Burkhard/0000-0002-1541-7867; Hartmann, Felix/0000-0002-4174-2276; Weber, Lukas M./0000-0002-3282-1730; Krieg, Carsten/0000-0002-5145-7591 FU University Research Priority Program (URPP) in Translational Cancer Research; Swiss National Science FoundationSwiss National Science Foundation (SNSF) [310030_146130, 316030_150768]; European UnionEuropean Union (EU); European Training Network MELGEN FX We thank V. Tosevski and T.M. Brodie (mass cytometry core facility, University of Zurich), A. Langer (Department of Dermatology, University of Zurich), and C. Beisel and K. Eschbach (Genomics Facility, ETH Basel) for excellent technical assistance and N. Nunes, B. Chatterjee, E. Terskikh, and C. Gujer (all from the Institute of Experimental Immunology, University Zurich), A. Zollinger (Swiss Institute of Bioinformatics, Lausanne), all members of the COST Action BM1404 Mye-EUNITER (http://www.mye-euniter.eu/), and P. Cheng (University of Zurich) for discussions. We also thank C. Guglietta for graphical design and layout. This work received funding from the University Research Priority Program (URPP) in Translational Cancer Research (C. K.), the Swiss National Science Foundation (grants 310030_146130 and 316030_150768; B. B.), the European Union FP7 project ATECT (B. B.), and the European Training Network MELGEN (M.P.L.). 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Med. PD FEB PY 2018 VL 24 IS 2 BP 144 EP + DI 10.1038/nm.4466 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA FV1MQ UT WOS:000424327200011 PM 29309059 OA Green Accepted DA 2020-07-01 ER PT J AU Bruggner, RV Bodenmiller, B Dill, DL Tibshirani, RJ Nolan, GP AF Bruggner, Robert V. Bodenmiller, Bernd Dill, David L. Tibshirani, Robert J. Nolan, Garry P. TI Automated identification of stratifying signatures in cellular subpopulations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE informatics; biomarker discovery ID FLOW-CYTOMETRY DATA; MASS CYTOMETRY; REGRESSION; RESPONSES; SELECTION; SUBSETS AB Elucidation and examination of cellular subpopulations that display condition-specific behavior can play a critical contributory role in understanding disease mechanism, as well as provide a focal point for development of diagnostic criteria linking such a mechanism to clinical prognosis. Despite recent advancements in single-cell measurement technologies, the identification of relevant cell subsets through manual efforts remains standard practice. As new technologies such as mass cytometry increase the parameterization of single-cell measurements, the scalability and subjectivity inherent in manual analyses slows both analysis and progress. We therefore developed Citrus (cluster identification, characterization, and regression), a data-driven approach for the identification of stratifying subpopulations in multidimensional cytometry datasets. The methodology of Citrus is demonstrated through the identification of known and unexpected pathway responses in a dataset of stimulated peripheral blood mononuclear cells measured by mass cytometry. Additionally, the performance of Citrus is compared with that of existing methods through the analysis of several publicly available datasets. As the complexity of flow cytometry datasets continues to increase, methods such as Citrus will be needed to aid investigators in the performance of unbiased-and potentially more thorough-correlation-based mining and inspection of cell subsets nested within high-dimensional datasets. C1 [Bruggner, Robert V.] Stanford Univ, Sch Med, Biomed Informat Training Program, Stanford, CA 94305 USA. [Bruggner, Robert V.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Dill, David L.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Tibshirani, Robert J.] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Tibshirani, Robert J.] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Bodenmiller, Bernd] Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland. C1 [Bruggner, Robert V.] Stanford Univ, Sch Med, Biomed Informat Training Program, Stanford, CA 94305 USA. [Bruggner, Robert V.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Dill, David L.] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Tibshirani, Robert J.] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Tibshirani, Robert J.] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Bodenmiller, Bernd] Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland. RP Tibshirani, RJ (reprint author), Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. EM tibs@stanford.edu; gnolan@stanford.edu EM tibs@stanford.edu; gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019 FU National Library of Medicine Training Grant [T15 LM007033]; Swiss National Science FoundationSwiss National Science Foundation (SNSF); European Molecular Biology OrganizationEuropean Molecular Biology Organization (EMBO); Marie Curie International Outgoing FellowshipEuropean Union (EU); National Cancer Institute GrantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U54CA149145]; National Science FoundationNational Science Foundation (NSF) [DMS-9971405]; National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [N01-HV-28183]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U54CA149145, UL1RR025744, 0158 G KB065, 1R01CA130826, 5U54CA143907, HHSN272200700038C, N01-HV-00242, 41000411217, 5 24927, P01 CA034233-22A1, PN2EY018228, RFA CA 09-009, RFA CA 09 011, U19 AI057229]; California Institute for Regenerative MedicineCalifornia Institute for Regenerative Medicine [DR1-01477, RB2-01592]; European CommissionEuropean Commission Joint Research Centre [HEALTH. 2010.1.2-1]; U.S. Food and Drug Administration [HHSF223201210194C: BAA-12-00118]; U.S. Department of DefenseUnited States Department of Defense [W81XWH-12-1-0591 OCRP-TIA NWC] FX We thank the two manuscript referees for their many helpful comments and feedback. We also wish to thank N. Kotecha for additional feedback on the manuscript, R. Finck for insight during method development, and M. Linderman for his work on the Rclusterpp R package. R.V.B. is supported by National Library of Medicine Training Grant T15 LM007033. B.B. is supported by grants from the Swiss National Science Foundation, the European Molecular Biology Organization, and a Marie Curie International Outgoing Fellowship. D.L.D. is supported by National Cancer Institute Grant U54CA149145. R.J.T. is supported by National Science Foundation Grant DMS-9971405 and National Institutes of Health (NIH) Grant N01-HV-28183. G.P.N. is supported by NIH Grants UL1RR025744, 0158 G KB065, 1R01CA130826, 5U54CA143907, HHSN272200700038C, N01-HV-00242, 41000411217, 5 24927, P01 CA034233-22A1, P01 CA034233-22A1, PN2EY018228, RFA CA 09-009, RFA CA 09 011, U19 AI057229, and U54CA149145; California Institute for Regenerative Medicine Grants DR1-01477 and RB2-01592; European Commission Grant HEALTH. 2010.1.2-1; U.S. Food and Drug Administration Grant HHSF223201210194C: BAA-12-00118; and U.S. Department of Defense Grant W81XWH-12-1-0591 OCRP-TIA NWC. 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Natl. Acad. Sci. U. S. A. PD JUL 1 PY 2014 VL 111 IS 26 BP E2770 EP E2777 DI 10.1073/pnas.1408792111 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK0QG UT WOS:000338118900020 PM 24979804 OA Green Published, Bronze DA 2020-07-01 ER PT J AU Simoni, Y Fehlings, M Kloverpris, HN McGovern, N Koo, SL Loh, CY Lim, S Kurioka, A Fergusson, JR Tang, CL Kam, MH Dennis, K Lim, TKH Fui, ACY Hoong, CW Chan, JKY de Lafaille, MC Narayanan, S Baig, S Shabeer, M Toh, SAES Tan, HKK Anicete, R Tan, EH Takano, A Klenerman, P Leslie, A Tan, DSW Tan, IB Ginhoux, F Newell, EW AF Simoni, Yannick Fehlings, Michael Kloverpris, Henrik N. McGovern, Naomi Koo, Si-Lin Loh, Chiew Yee Lim, Shawn Kurioka, Ayako Fergusson, Joannah R. 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Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie) ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues. C1 [Simoni, Yannick; Fehlings, Michael; McGovern, Naomi; Loh, Chiew Yee; Lim, Shawn; de Lafaille, Maria Curotto; Ginhoux, Florent; Newell, Evan W.] Agcy Sci Technol & Res, Singapore Immunol Network SIgN, Singapore 138648, Singapore. [Kloverpris, Henrik N.; Leslie, Alasdair] Africa Hlth Res Inst, ZA-4001 Durban, South Africa. [Kloverpris, Henrik N.] Univ Copenhagen, Dept Immunol & Microbiol, DK-1165 Copenhagen, Denmark. [Koo, Si-Lin; Tan, Eng-Huat; Tan, Daniel S. W.; Tan, Iain Beehuat] Natl Canc Ctr Singapore, Div Med Oncol, Singapore 169610, Singapore. [Kurioka, Ayako; Fergusson, Joannah R.; Klenerman, Paul] Univ Oxford, Peter Medawar Bldg Pathogen Res, Oxford OX1 3SY, England. [Tang, Choong-Leong; Kam, Ming Hian; Dennis, Koh] Singapore Gen Hosp, Dept Colorectal Surg, Singapore 169856, Singapore. [Dennis, Koh] Mt Elizabeth Med Ctr, Colorectal Practice, Singapore 228510, Singapore. [Lim, Tony Kiat Hon; Takano, Angela] Singapore Gen Hosp, Dept Anat Pathol, Singapore 169608, Singapore. [Fui, Alexander Chung Yaw] Singapore Gen Hosp, Dept Hepatopancreatobiliary Transplant Surg, Singapore 169608, Singapore. [Hoong, Chan Weng] Singapore Gen Hosp, Dept Upper GI Bariatr Surg, Singapore 169608, Singapore. [Chan, Jerry Kok Yen] KK Womens & Childrens Hosp, Dept Reprod Med, Singapore 229899, Singapore. [Chan, Jerry Kok Yen; Toh, Sue-Anne Ee Shiow; Tan, Iain Beehuat] Duke NUS Grad Med Sch, Singapore 169857, Singapore. [Narayanan, Sriram] Agcy Sci Technol & Res, Inst Mol & Cell Biol, Singapore 138673, Singapore. [Baig, Sonia; Toh, Sue-Anne Ee Shiow] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 119228, Singapore. [de Lafaille, Maria Curotto] NYU, Sch Med, 550 1st Ave, New York, NY 10012 USA. [Toh, Sue-Anne Ee Shiow] Natl Univ Hlth Syst, Dept Med, Singapore 119228, Singapore. [Toh, Sue-Anne Ee Shiow] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Tan, Henry Kun Kiaang; Anicete, Rosslyn] KK Womens & Childrens Hosp, Dept Otolaryngol, Singapore 229899, Singapore. [Tan, Daniel S. W.; Tan, Iain Beehuat] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore 138672, Singapore. C1 [Simoni, Yannick; Fehlings, Michael; McGovern, Naomi; Loh, Chiew Yee; Lim, Shawn; de Lafaille, Maria Curotto; Ginhoux, Florent; Newell, Evan W.] Agcy Sci Technol & Res, Singapore Immunol Network SIgN, Singapore 138648, Singapore. [Kloverpris, Henrik N.; Leslie, Alasdair] Africa Hlth Res Inst, ZA-4001 Durban, South Africa. [Kloverpris, Henrik N.] Univ Copenhagen, Dept Immunol & Microbiol, DK-1165 Copenhagen, Denmark. [Koo, Si-Lin; Tan, Eng-Huat; Tan, Daniel S. W.; Tan, Iain Beehuat] Natl Canc Ctr Singapore, Div Med Oncol, Singapore 169610, Singapore. [Kurioka, Ayako; Fergusson, Joannah R.; Klenerman, Paul] Univ Oxford, Peter Medawar Bldg Pathogen Res, Oxford OX1 3SY, England. [Tang, Choong-Leong; Kam, Ming Hian; Dennis, Koh] Singapore Gen Hosp, Dept Colorectal Surg, Singapore 169856, Singapore. [Dennis, Koh] Mt Elizabeth Med Ctr, Colorectal Practice, Singapore 228510, Singapore. [Lim, Tony Kiat Hon; Takano, Angela] Singapore Gen Hosp, Dept Anat Pathol, Singapore 169608, Singapore. [Fui, Alexander Chung Yaw] Singapore Gen Hosp, Dept Hepatopancreatobiliary Transplant Surg, Singapore 169608, Singapore. [Hoong, Chan Weng] Singapore Gen Hosp, Dept Upper GI Bariatr Surg, Singapore 169608, Singapore. [Chan, Jerry Kok Yen] KK Womens & Childrens Hosp, Dept Reprod Med, Singapore 229899, Singapore. [Chan, Jerry Kok Yen; Toh, Sue-Anne Ee Shiow; Tan, Iain Beehuat] Duke NUS Grad Med Sch, Singapore 169857, Singapore. [Narayanan, Sriram] Agcy Sci Technol & Res, Inst Mol & Cell Biol, Singapore 138673, Singapore. [Baig, Sonia; Toh, Sue-Anne Ee Shiow] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 119228, Singapore. [de Lafaille, Maria Curotto] NYU, Sch Med, 550 1st Ave, New York, NY 10012 USA. [Toh, Sue-Anne Ee Shiow] Natl Univ Hlth Syst, Dept Med, Singapore 119228, Singapore. [Toh, Sue-Anne Ee Shiow] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Tan, Henry Kun Kiaang; Anicete, Rosslyn] KK Womens & Childrens Hosp, Dept Otolaryngol, Singapore 229899, Singapore. [Tan, Daniel S. W.; Tan, Iain Beehuat] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore 138672, Singapore. RP Simoni, Y (reprint author), Agcy Sci Technol & Res, Singapore Immunol Network SIgN, Singapore 138648, Singapore. EM yannick_simoni@immunol.a-star.edu.sg; evan_newell@immunol.a-star.edu.sg EM yannick_simoni@immunol.a-star.edu.sg; evan_newell@immunol.a-star.edu.sg RI Newell, Evan W/F-9711-2012; Newell, Evan/AAE-9470-2020 OI Newell, Evan W/0000-0002-2889-243X; Newell, Evan/0000-0002-2889-243X; leslie, alasdair/0000-0003-2538-6467; McGovern, Naomi/0000-0001-5200-2698; Koo, Si-Lin/0000-0002-8217-3321; Kloverpris, Henrik/0000-0002-2165-3313 FU A-STAR/SIgN core funding; A-STAR/SIgN immunomonitoring platform funding; Translational & Clinical Research grand from the National Medical Research Council, Singapore [NMRC/TCR/007-NCC/2013]; National Cancer Center Singapore [CG/007/2013-SD2 (NCCSPG-YR2015-JUL-13)]; NIHR Biomedical Research Centre, OxfordNational Institute for Health Research (NIHR); NIHR Senior Fellowship; [WT109965MA]; Lundbeck FoundationLundbeckfonden [R151-2013-14624]; National Institute for Health ResearchNational Institute for Health Research (NIHR) [NF-SI-0515-10005] FX The authors thank all members of E.N. and F.G. laboratory, Etienne Becht, Harsimran Singh, the SIgN community, and the SIgN flow cytometry and luminex facilities. This study was funded by A-STAR/SIgN core funding, A-STAR/SIgN immunomonitoring platform funding, a Translational & Clinical Research grand from the National Medical Research Council, Singapore (NMRC/TCR/007-NCC/2013) and the National Cancer Center Singapore CG/007/2013-SD2 (NCCSPG-YR2015-JUL-13). P.K. is supported by NIHR Biomedical Research Centre, Oxford, an NIHR Senior Fellowship and WT109965MA. 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Finck, Rachel Behbehani, Gregory K. Amir, El-ad D. Krishnaswamy, Smita Gonzalez, Veronica D. Lorang, Cynthia G. Bjornson, Zach Spitzer, Matthew H. Bodenmiller, Bernd Fantl, Wendy J. Pe'er, Dana Nolan, Garry P. TI Palladium-based mass tag cell barcoding with a doublet-filtering scheme and single-cell deconvolution algorithm SO NATURE PROTOCOLS LA English DT Article ID CYTOMETRY DATA; SAMPLES AB Mass-tag cell barcoding (MCB) labels individual cell samples with unique combinatorial barcodes, after which they are pooled for processing and measurement as a single multiplexed sample. The MCB method eliminates variability between samples in antibody staining and instrument sensitivity, reduces antibody consumption and shortens instrument measurement time. Here we present an optimized MCB protocol. The use of palladium-based labeling reagents expands the number of measurement channels available for mass cytometry and reduces interference with lanthanide-based antibody measurement. An error-detecting combinatorial barcoding scheme allows cell doublets to be identified and removed from the analysis. A debarcoding algorithm that is single cell-based rather than population-based improves the accuracy and efficiency of sample deconvolution. This debarcoding algorithm has been packaged into software that allows rapid and unbiased sample deconvolution. The MCB procedure takes 3-4 h, not including sample acquisition time of similar to 1 h per million cells. C1 [Zunder, Eli R.; Finck, Rachel; Behbehani, Gregory K.; Gonzalez, Veronica D.; Lorang, Cynthia G.; Bjornson, Zach; Spitzer, Matthew H.; Bodenmiller, Bernd; Fantl, Wendy J.; Nolan, Garry P.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Behbehani, Gregory K.] Stanford Univ, Sch Med, Div Hematol, Stanford, CA 94305 USA. [Behbehani, Gregory K.] Stanford Univ, Sch Med, Div Oncol, Stanford, CA 94305 USA. [Amir, El-ad D.; Krishnaswamy, Smita; Pe'er, Dana] Columbia Univ, Dept Biol Sci, Dept Syst Biol, New York, NY 10027 USA. C1 [Zunder, Eli R.; Finck, Rachel; Behbehani, Gregory K.; Gonzalez, Veronica D.; Lorang, Cynthia G.; Bjornson, Zach; Spitzer, Matthew H.; Bodenmiller, Bernd; Fantl, Wendy J.; Nolan, Garry P.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Behbehani, Gregory K.] Stanford Univ, Sch Med, Div Hematol, Stanford, CA 94305 USA. [Behbehani, Gregory K.] Stanford Univ, Sch Med, Div Oncol, Stanford, CA 94305 USA. [Amir, El-ad D.; Krishnaswamy, Smita; Pe'er, Dana] Columbia Univ, Dept Biol Sci, Dept Syst Biol, New York, NY 10027 USA. RP Nolan, GP (reprint author), Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. EM gnolan@stanford.edu EM gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019 OI Spitzer, Matthew/0000-0002-5291-3819; Pe'er, Dana/0000-0002-9259-8817 FU US National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19 AI057229, U54CA149145, N01-HV-00242, 1U19AI100627, 5R01AI07372405, R01CA184968, 1 R33 CA183654, NRSA F32 GM093508-01, 152175.5041015.0412, R01 A1073724]; NIH-the Baylor Research Institute [41000411217]; NIH-Northrop Grumman Corp. [7500108142]; California Institute for Regenerative Medicine (CIRM)California Institute for Regenerative Medicine [DR1-01477, RB2-01592]; US Department of DefenseUnited States Department of Defense [OC110674]; European CommissionEuropean Commission Joint Research Centre [Health.2010.1.2-1]; US Food and Drug Administration [HHSF223201210194C]; Bill and Melinda Gates FoundationGates Foundation [OPP 1017093]; Alliance for Lupus Research, the Lymphoma Research Foundation; Entertainment Industry Foundation (National Women's Cancer Research Alliance grant); National Science Foundation CAREER awardNational Science Foundation (NSF) [MCB-1149728]; Packard Fellowship for Science and Engineering; Rachford and Carlota A. Harris Endowed Professorship FX We thank A. Trejo and A. Jager for mass cytometry quality control and instrument maintenance. We thank E. Simonds and P. Krutzik for their helpful discussions. This work was supported by grants from the US National Institutes of Health (NIH) (U19 AI057229, U54CA149145, N01-HV-00242, 1U19AI100627, 5R01AI07372405, R01CA184968, 1 R33 CA183654, NRSA F32 GM093508-01, 152175.5041015.0412 and R01 A1073724), NIH-the Baylor Research Institute (41000411217), the NIH-Northrop Grumman Corp. (7500108142), the California Institute for Regenerative Medicine (CIRM) (DR1-01477, RB2-01592), the US Department of Defense (OC110674), the European Commission (Health.2010.1.2-1), the US Food and Drug Administration (HHSF223201210194C), the Bill and Melinda Gates Foundation (OPP 1017093), the Alliance for Lupus Research, the Lymphoma Research Foundation, the Entertainment Industry Foundation (National Women's Cancer Research Alliance grant) and the National Science Foundation CAREER award (MCB-1149728). D.P. holds a Packard Fellowship for Science and Engineering. G.P.N. holds the Rachford and Carlota A. Harris Endowed Professorship. CR Amir ED, 2013, NAT BIOTECHNOL, V31, P545, DOI 10.1038/nbt.2594 Bandura DR, 2009, ANAL CHEM, V81, P6813, DOI 10.1021/ac901049w Behbehani GK, 2014, CYTOM PART A, V85A, P1011, DOI 10.1002/cyto.a.22573 Bodenmiller B, 2012, NAT BIOTECHNOL, V30, P858, DOI 10.1038/nbt.2317 Bruggner RV, 2014, P NATL ACAD SCI USA, V111, pE2770, DOI 10.1073/pnas.1408792111 Finck R, 2013, CYTOM PART A, V83A, P483, DOI 10.1002/cyto.a.22271 Fulton RJ, 1997, CLIN CHEM, V43, P1749 Hamady M, 2008, NAT METHODS, V5, P235, DOI [10.1038/nmeth.1184, 10.1038/NMETH.1184] Krutzik PO, 2006, NAT METHODS, V3, P361, DOI 10.1038/NMETH872 Majonis D, 2011, BIOMACROMOLECULES, V12, P3997, DOI 10.1021/bm201011t Meyer M, 2007, NUCLEIC ACIDS RES, V35, DOI 10.1093/nar/gkm566 Parameswaran P, 2007, NUCLEIC ACIDS RES, V35, DOI 10.1093/nar/gkm760 Qiu P, 2011, NAT BIOTECHNOL, V29, P886, DOI 10.1038/nbt.1991 NR 13 TC 162 Z9 161 U1 1 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD FEB PY 2015 VL 10 IS 2 BP 316 EP 333 DI 10.1038/nprot.2015.020 PG 18 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA CE6ET UT WOS:000351930100007 PM 25612231 OA Green Accepted DA 2020-07-01 ER PT J AU Swadling, L Capone, S Antrobus, RD Brown, A Richardson, R Newell, EW Halliday, J Kelly, C Bowen, D Fergusson, J Kurioka, A Ammendola, V Del Sorbo, M Grazioli, F Esposito, ML Siani, L Traboni, C Hill, A Colloca, S Davis, M Nicosia, A Cortese, R Folgori, A Klenerman, P Barnes, E AF Swadling, Leo Capone, Stefania Antrobus, Richard D. Brown, Anthony Richardson, Rachel Newell, Evan W. Halliday, John Kelly, Christabel Bowen, Dan Fergusson, Joannah Kurioka, Ayako Ammendola, Virginia Del Sorbo, Mariarosaria Grazioli, Fabiana Esposito, Maria Luisa Siani, Loredana Traboni, Cinzia Hill, Adrian Colloca, Stefano Davis, Mark Nicosia, Alfredo Cortese, Riccardo Folgori, Antonella Klenerman, Paul Barnes, Eleanor TI A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID HEPATITIS-C VIRUS; SINGLE-SOURCE OUTBREAK; IMMUNE-RESPONSES; VIRAL CLEARANCE; NEUTRALIZING ANTIBODIES; CYTOKINE EXPRESSION; ACUTE INFECTION; STAGE MALARIA; PERSISTENCE; CHALLENGE AB A protective vaccine against hepatitis C virus (HCV) remains an unmet clinical need. HCV infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular cancer. Animal challenge experiments, immunogenetics studies, and assessment of host immunity during acute infection highlight the critical role that effective T cell immunity plays in viral control. In this first-in-man study, we have induced antiviral immunity with functional characteristics analogous to those associated with viral control in natural infection, and improved upon a vaccine based on adenoviral vectors alone. We assessed a heterologous prime-boost vaccination strategy based on a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A, and NS5B proteins of HCV genotype 1b. Analysis used single-cell mass cytometry and human leukocyte antigen class I peptide tetramer technology in healthy human volunteers. We show that HCV-specific T cells induced by ChAd3 are optimally boosted with MVA, and generate very high levels of both CD8(+) and CD4(+) HCV-specific T cells targeting multiple HCV antigens. Sustained memory and effector T cell populations are generated, and T cell memory evolved over time with improvement of quality (proliferation and polyfunctionality) after heterologous MVA boost. We have developed an HCV vaccine strategy, with durable, broad, sustained, and balanced T cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine. C1 [Swadling, Leo; Antrobus, Richard D.; Brown, Anthony; Richardson, Rachel; Halliday, John; Kelly, Christabel; Bowen, Dan; Fergusson, Joannah; Kurioka, Ayako; Hill, Adrian; Klenerman, Paul; Barnes, Eleanor] Univ Oxford, Nuffield Dept Med, Oxford OX1 3SY, England. [Capone, Stefania; Ammendola, Virginia; Del Sorbo, Mariarosaria; Grazioli, Fabiana; Esposito, Maria Luisa; Siani, Loredana; Traboni, Cinzia; Colloca, Stefano; Nicosia, Alfredo; Folgori, Antonella] ReiThera Srl Ex Okairos, I-00144 Rome, Italy. [Antrobus, Richard D.; Hill, Adrian; Barnes, Eleanor] Univ Oxford, Jenner Inst, Oxford OX3 7DQ, England. [Newell, Evan W.; Davis, Mark] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Newell, Evan W.] Singapore Immunol Network, Singapore 138648, Singapore. [Halliday, John; Kelly, Christabel; Klenerman, Paul; Barnes, Eleanor] Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford OX3 7LE, England. [Halliday, John; Kelly, Christabel; Klenerman, Paul; Barnes, Eleanor] Translat Gastroenterol Unit, Oxford OX3 7LE, England. [Nicosia, Alfredo] CEINGE, I-80145 Naples, Italy. [Nicosia, Alfredo] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy. [Cortese, Riccardo] Okairos AG, CH-4051 Basel, Switzerland. C1 [Swadling, Leo; Antrobus, Richard D.; Brown, Anthony; Richardson, Rachel; Halliday, John; Kelly, Christabel; Bowen, Dan; Fergusson, Joannah; Kurioka, Ayako; Hill, Adrian; Klenerman, Paul; Barnes, Eleanor] Univ Oxford, Nuffield Dept Med, Oxford OX1 3SY, England. [Capone, Stefania; Ammendola, Virginia; Del Sorbo, Mariarosaria; Grazioli, Fabiana; Esposito, Maria Luisa; Siani, Loredana; Traboni, Cinzia; Colloca, Stefano; Nicosia, Alfredo; Folgori, Antonella] ReiThera Srl Ex Okairos, I-00144 Rome, Italy. [Antrobus, Richard D.; Hill, Adrian; Barnes, Eleanor] Univ Oxford, Jenner Inst, Oxford OX3 7DQ, England. [Newell, Evan W.; Davis, Mark] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Newell, Evan W.] Singapore Immunol Network, Singapore 138648, Singapore. [Halliday, John; Kelly, Christabel; Klenerman, Paul; Barnes, Eleanor] Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford OX3 7LE, England. [Halliday, John; Kelly, Christabel; Klenerman, Paul; Barnes, Eleanor] Translat Gastroenterol Unit, Oxford OX3 7LE, England. [Nicosia, Alfredo] CEINGE, I-80145 Naples, Italy. [Nicosia, Alfredo] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy. [Cortese, Riccardo] Okairos AG, CH-4051 Basel, Switzerland. RP Barnes, E (reprint author), Univ Oxford, Nuffield Dept Med, Oxford OX1 3SY, England. EM ellie.barnes@ndm.ox.ac.uk EM ellie.barnes@ndm.ox.ac.uk RI Newell, Evan/AAE-9470-2020; Newell, Evan W/F-9711-2012; Swadling, Leo/Y-5141-2019 OI Newell, Evan/0000-0002-2889-243X; Newell, Evan W/0000-0002-2889-243X; Swadling, Leo/0000-0002-0537-6715; Capone, Stefania/0000-0002-2272-120X; Barnes, Eleanor/0000-0002-0860-0831; Fergusson, Joannah/0000-0001-9223-1209 FU Medical Research Council (MRC) UKMedical Research Council UK (MRC); European Union (Framework VI; HEPACIVAC); MRC UK DCS (Developmental Clinical Studies) award; Oxford Martin Schools; National Institute for Health Research Oxford Biomedical Research CentreNational Institute for Health Research (NIHR); MRC CASE studentship; MRCMedical Research Council UK (MRC); Medical Research CouncilMedical Research Council UK (MRC) [MR/K010239/1]; National Institute for Health ResearchNational Institute for Health Research (NIHR) [NF-SI-0510-10204] FX Supported by the Medical Research Council (MRC) UK and the European Union (Framework VI; HEPACIVAC) for funding the study and the manufacture of MVA-NSmut through an MRC UK DCS (Developmental Clinical Studies) award. E.B. is supported by the MRC as a Senior Clinical Fellow, the Oxford Martin Schools, and National Institute for Health Research Oxford Biomedical Research Centre. L. Swadling is supported by an MRC CASE studentship. 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Transl. Med. PD NOV 5 PY 2014 VL 6 IS 261 AR 261ra153 DI 10.1126/scitranslmed.3009185 PG 16 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AS4GR UT WOS:000344232400007 PM 25378645 OA Green Accepted DA 2020-07-01 ER PT J AU Gaudilliere, B Fragiadakis, GK Bruggner, RV Nicolau, M Finck, R Tingle, M Silva, J Ganio, EA Yeh, CG Maloney, WJ Huddleston, JI Goodman, SB Davis, MM Bendall, SC Fantl, WJ Angst, MS Nolan, GP AF Gaudilliere, Brice Fragiadakis, Gabriela K. Bruggner, Robert V. Nicolau, Monica Finck, Rachel Tingle, Martha Silva, Julian Ganio, Edward A. Yeh, Christine G. Maloney, William J. Huddleston, James I. Goodman, Stuart B. Davis, Mark M. Bendall, Sean C. Fantl, Wendy J. Angst, Martin S. Nolan, Garry P. TI Clinical recovery from surgery correlates with single-cell immune signatures SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NF-KAPPA-B; MASS CYTOMETRY; SEPTIC PATIENTS; EXPRESSION; STRESS; CONVALESCENCE; VALIDATION; PATHWAYS; OUTCOMES; SEPSIS AB Delayed recovery from surgery causes personal suffering and substantial societal and economic costs. Whether immune mechanisms determine recovery after surgical trauma remains ill-defined. Single-cell mass cytometry was applied to serial whole-blood samples from 32 patients undergoing hip replacement to comprehensively characterize the phenotypic and functional immune response to surgical trauma. The simultaneous analysis of 14,000 phosphorylation events in precisely phenotyped immune cell subsets revealed uniform signaling responses among patients, demarcating a surgical immune signature. When regressed against clinical parameters of surgical recovery, including functional impairment and pain, strong correlations were found with STAT3 (signal transducer and activator of transcription), CREB (adenosine 3',5'-monophosphate response element-binding protein), and NF-kappa B (nuclear factor kappa B) signaling responses in subsets of CD14(+) monocytes (R = 0.7 to 0.8, false discovery rate <0.01). These sentinel results demonstrate the capacity of mass cytometry to survey the human immune system in a relevant clinical context. The mechanistically derived immune correlates point to diagnostic signatures, and potential therapeutic targets, that could postoperatively improve patient recovery. C1 [Gaudilliere, Brice; Tingle, Martha; Silva, Julian; Ganio, Edward A.; Yeh, Christine G.; Angst, Martin S.] Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA. [Gaudilliere, Brice; Fragiadakis, Gabriela K.; Bruggner, Robert V.; Nicolau, Monica; Finck, Rachel; Bendall, Sean C.; Fantl, Wendy J.; Nolan, Garry P.] Stanford Univ, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Fragiadakis, Gabriela K.; Finck, Rachel; Davis, Mark M.; Bendall, Sean C.; Fantl, Wendy J.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Bruggner, Robert V.] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA. [Nicolau, Monica] Stanford Univ, Dept Math, Stanford, CA 94305 USA. [Nicolau, Monica] Stanford Univ, Ctr Canc Syst Biol, Stanford, CA 94305 USA. [Maloney, William J.; Huddleston, James I.; Goodman, Stuart B.] Stanford Univ, Dept Orthoped Surg, Redwood City, CA 94063 USA. [Fantl, Wendy J.] Stanford Univ, Dept Obstet & Gynecol, Stanford, CA 94305 USA. C1 [Gaudilliere, Brice; Tingle, Martha; Silva, Julian; Ganio, Edward A.; Yeh, Christine G.; Angst, Martin S.] Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA. [Gaudilliere, Brice; Fragiadakis, Gabriela K.; Bruggner, Robert V.; Nicolau, Monica; Finck, Rachel; Bendall, Sean C.; Fantl, Wendy J.; Nolan, Garry P.] Stanford Univ, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Fragiadakis, Gabriela K.; Finck, Rachel; Davis, Mark M.; Bendall, Sean C.; Fantl, Wendy J.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Bruggner, Robert V.] Stanford Univ, Biomed Informat Program, Stanford, CA 94305 USA. [Nicolau, Monica] Stanford Univ, Dept Math, Stanford, CA 94305 USA. [Nicolau, Monica] Stanford Univ, Ctr Canc Syst Biol, Stanford, CA 94305 USA. [Maloney, William J.; Huddleston, James I.; Goodman, Stuart B.] Stanford Univ, Dept Orthoped Surg, Redwood City, CA 94063 USA. [Fantl, Wendy J.] Stanford Univ, Dept Obstet & Gynecol, Stanford, CA 94305 USA. RP Angst, MS (reprint author), Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA. EM ang@stanford.edu; gnolan@stanford.edu EM ang@stanford.edu; gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019 FU NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [T32GM089626, T32GM007276, 5T15LM007033-27, 1K99GM104148-01, UL1RR025744, 1R01CA130826, 5U54CA143907, HHSN272200700038C, N01-HV-00242, 41000411217, 1U19AI100627, P01CA034233-22A1, U19AI057229, U54CA149145, S10RR027582-01]; Stanford Society of Physician Scholars grant; Stanford Bio-X graduate research fellowship; Damon Runyon Cancer Research Foundation Fellowship [DRG-2017-09]; Food and Drug AdministrationUnited States Department of Health & Human Services [HHSF223201210194C]; National Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U54 CA149145]; Stanford Department of Anesthesiology, Perioperative and Pain Medicine; California Institute for Regenerative MedicineCalifornia Institute for Regenerative Medicine [DR1-01477, RB2-01592]; European CommissionEuropean Commission Joint Research Centre [HEALTH.2010.1.2-1]; U.S. Department of DefenseUnited States Department of Defense [W81XWH-12-1-0591 OCRP-TIA NWC] FX Supported by funds from NIH T32GM089626 and the Stanford Society of Physician Scholars grant (B.G.); the Stanford Bio-X graduate research fellowship and NIH T32GM007276 (G.K.F.); NIH 5T15LM007033-27 (R.V.B.); the Damon Runyon Cancer Research Foundation Fellowship (DRG-2017-09) and NIH 1K99GM104148-01 (S.C.B.); the Food and Drug Administration Contract HHSF223201210194C and National Cancer Institute U54 CA149145 (M.N.); and the Stanford Department of Anesthesiology, Perioperative and Pain Medicine (M.S.A.). G.P.N. is supported by funds from NIH grants UL1RR025744, 1R01CA130826, 5U54CA143907, HHSN272200700038C, N01-HV-00242, 41000411217, 1U19AI100627, P01CA034233-22A1, U19AI057229, U54CA149145, and S10RR027582-01; the California Institute for Regenerative Medicine (DR1-01477 and RB2-01592); the European Commission (HEALTH.2010.1.2-1); and the U.S. Department of Defense (W81XWH-12-1-0591 OCRP-TIA NWC). 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Transl. Med. PD SEP 24 PY 2014 VL 6 IS 255 AR 255ra131 DI 10.1126/scitranslmed.3009701 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AR1BY UT WOS:000343316800006 PM 25253674 OA Green Accepted DA 2020-07-01 ER PT J AU Macaulay, IC Ponting, CP Voet, T AF Macaulay, Iain C. Ponting, Chris P. Voet, Thierry TI Single-Cell Multiomics: Multiple Measurements from Single Cells SO TRENDS IN GENETICS LA English DT Review ID GENOME-WIDE DETECTION; RNA-SEQ; MESSENGER-RNA; DNA-METHYLATION; MASS CYTOMETRY; TRANSCRIPTOME; PROTEINS; HETEROGENEITY; STEM; VARIABILITY AB Single-cell sequencing provides information that is not confounded by genotypic or phenotypic heterogeneity of bulk samples. Sequencing of one molecular type (RNA, methylated DNA or open chromatin) in a single cell, furthermore, provides insights into the cell's phenotype and links to its genotype. Nevertheless, only by taking measurements of these phenotypes and genotypes from the same single cells can such inferences be made unambiguously. In this review, we survey the first experimental approaches that assay, in parallel, multiple molecular types from the same single cell, before considering the challenges and opportunities afforded by these and future technologies. C1 [Macaulay, Iain C.] Norwich Res Pk, Earlham Inst, Norwich NR4 7UH, Norfolk, England. [Ponting, Chris P.; Voet, Thierry] Wellcome Trust Sanger Inst, Sanger Inst EBI, Single Cell Genom Ctr, Hinxton CB10 1SA, England. [Ponting, Chris P.] Univ Edinburgh, MRC, MRC IGMM, Human Genet Unit, Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland. [Voet, Thierry] Univ Leuven, Dept Human Genet, KU Leuven, B-3000 Leuven, Belgium. C1 [Macaulay, Iain C.] Norwich Res Pk, Earlham Inst, Norwich NR4 7UH, Norfolk, England. [Ponting, Chris P.; Voet, Thierry] Wellcome Trust Sanger Inst, Sanger Inst EBI, Single Cell Genom Ctr, Hinxton CB10 1SA, England. [Ponting, Chris P.] Univ Edinburgh, MRC, MRC IGMM, Human Genet Unit, Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland. [Voet, Thierry] Univ Leuven, Dept Human Genet, KU Leuven, B-3000 Leuven, Belgium. RP Macaulay, IC (reprint author), Norwich Res Pk, Earlham Inst, Norwich NR4 7UH, Norfolk, England.; Ponting, CP; Voet, T (reprint author), Wellcome Trust Sanger Inst, Sanger Inst EBI, Single Cell Genom Ctr, Hinxton CB10 1SA, England.; Ponting, CP (reprint author), Univ Edinburgh, MRC, MRC IGMM, Human Genet Unit, Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland.; Voet, T (reprint author), Univ Leuven, Dept Human Genet, KU Leuven, B-3000 Leuven, Belgium. EM lain.Macaulay@earlham.ac.uk; Chris.Ponting@igmm.ed.ac.uk; thierry.voet@kuleuven.be EM lain.Macaulay@earlham.ac.uk; Chris.Ponting@igmm.ed.ac.uk; thierry.voet@kuleuven.be RI Voet, Thierry/E-8877-2017 OI Macaulay, Iain/0000-0002-6761-757X FU Wellcome TrustWellcome Trust; BBSRCBiotechnology and Biological Sciences Research Council (BBSRC); MRCMedical Research Council UK (MRC); University of Leuven (KU Leuven, Belgium; SymBioSys) [PFV/10/016]; FWOFWO [G.0687.12, G.0924.15]; Medical Research CouncilMedical Research Council UK (MRC) [MC_PC_15075, MC_UU_12008/1] FX Single-cell research and development at the Wellcome Trust Sanger Institute by C.P.P. and T.V. is funded by the Wellcome Trust. Single-cell technology development at the Earlham Institute by I.C.M. is funded by the BBSRC. C.P.P. research is also funded by the MRC. T.V. is also funded by the University of Leuven (KU Leuven, Belgium; SymBioSys, PFV/10/016) and the FWO (G.0687.12 and G.0924.15). We thank our colleagues at the WTSI/EBI Single Cell Genomics Centre for lively and helpful discussions. 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PD FEB PY 2017 VL 33 IS 2 BP 155 EP 168 DI 10.1016/j.tig.2016.12.003 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA EK0RU UT WOS:000393635600007 PM 28089370 OA Green Published, Other Gold DA 2020-07-01 ER PT J AU Newell, EW Sigal, N Nair, N Kidd, BA Greenberg, HB Davis, MM AF Newell, Evan W. Sigal, Natalia Nair, Nitya Kidd, Brian A. Greenberg, Harry B. Davis, Mark M. TI Combinatorial tetramer staining and mass cytometry analysis facilitate T-cell epitope mapping and characterization SO NATURE BIOTECHNOLOGY LA English DT Article ID CLASS-I LIGANDS; MHC TETRAMERS; MEMORY; EXPRESSION; DIVERSITY; CONTINUUM; RESPONSES; PROTEIN; IMMUNE AB It is currently not possible to predict which epitopes will be recognized by T cells in different individuals. This is a barrier to the thorough analysis and understanding of T-cell responses after vaccination or infection. Here, by combining mass cytometry with combinatorial peptide-MHC tetramer staining, we have developed a method allowing the rapid and simultaneous identification and characterization of T cells specific for many epitopes. We use this to screen up to 109 different peptide-MHC tetramers in a single human blood sample, while still retaining at least 23 labels to analyze other markers of T-cell phenotype and function. Among 77 candidate rotavirus epitopes, we identified six T-cell epitopes restricted to human leukocyte antigen (HLA)-A*0201 in the blood of healthy individuals. T cells specific for epitopes in the rotavirus VP3 protein displayed a distinct phenotype and were present at high frequencies in intestinal epithelium. This approach should be useful for the comprehensive analysis of T-cell responses to infectious diseases or vaccines. C1 [Newell, Evan W.] ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore. [Newell, Evan W.; Nair, Nitya; Greenberg, Harry B.; Davis, Mark M.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Sigal, Natalia; Kidd, Brian A.; Greenberg, Harry B.; Davis, Mark M.] Stanford Univ, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. [Nair, Nitya; Greenberg, Harry B.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Davis, Mark M.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. C1 [Newell, Evan W.] ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore. [Newell, Evan W.; Nair, Nitya; Greenberg, Harry B.; Davis, Mark M.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Sigal, Natalia; Kidd, Brian A.; Greenberg, Harry B.; Davis, Mark M.] Stanford Univ, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. [Nair, Nitya; Greenberg, Harry B.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Davis, Mark M.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. RP Davis, MM (reprint author), Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. EM evan_newell@immunol.a-star.edu.sg; mmdavis@stanford.edu EM evan_newell@immunol.a-star.edu.sg; mmdavis@stanford.edu RI Nair, Nitya/D-2651-2017; Newell, Evan/AAE-9470-2020; Newell, Evan W/F-9711-2012 OI Nair, Nitya/0000-0002-9524-9313; Newell, Evan/0000-0002-2889-243X; Newell, Evan W/0000-0002-2889-243X; Kidd, Brian/0000-0003-2110-1145; greenberg, harry/0000-0002-2128-9080 FU Bill and Melinda Gates FoundationGates Foundation; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19-AI057229, U19-AI090019]; Howard Hughes Medical InstituteHoward Hughes Medical Institute; American Cancer SocietyAmerican Cancer Society; Singapore Immunology NetworkAgency for Science Technology & Research (ASTAR) FX We thank members of the Davis, Holden Maecker and Garry Nolan labs for sharing advice and experience concerning mass cytometry and antibody clone usage, especially M. Leipold for help with the mass cytometry instrument, and X. He, F. Wen, W. O'Gorman, A. Han, S. Bendall, O. Goldberger and Y.-H. Chien for helpful discussions. This work was supported by the Bill and Melinda Gates Foundation Grand Challenges Exploration phase I and II grants, National Institutes of Health grants U19-AI057229 and U19-AI090019, and The Howard Hughes Medical Institute. E.W.N. was supported by The American Cancer Society's Steven Stanley and Edward Albert Bielfelt Post-Doctoral Fellowship and by funding through the Singapore Immunology Network. 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Biotechnol. PD JUL PY 2013 VL 31 IS 7 BP 623 EP U81 DI 10.1038/nbt.2593 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 180FS UT WOS:000321579700019 PM 23748502 OA Green Accepted DA 2020-07-01 ER PT J AU Brodin, P Davis, MM AF Brodin, Petter Davis, Mark M. TI Human immune system variation SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID DELTA T-CELLS; MASS CYTOMETRY; RHEUMATOID-ARTHRITIS; CIRCADIAN-RHYTHMS; PERIPHERAL-BLOOD; SEX-DIFFERENCES; EXPRESSION; DISEASE; AUTOIMMUNE; MICROBIOTA AB The human immune system is highly variable between individuals but relatively stable over time within a given person. Recent conceptual and technological advances have enabled systems immunology analyses, which reveal the composition of immune cells and proteins in populations of healthy individuals. The range of variation and some specific influences that shape an individual's immune system is now becoming clearer. Human immune systems vary as a consequence of heritable and non-heritable influences, but symbiotic and pathogenic microbes and other non-heritable influences explain most of this variation. Understanding when and how such influences shape the human immune system is key for defining metrics of immunological health and understanding the risk of immune-mediated and infectious diseases. C1 [Brodin, Petter] Karolinska Inst, Dept Med Solna, Sci Life Lab, S-17165 Stockholm, Sweden. [Brodin, Petter] Karolinska Univ Hosp, Dept Neonatol, S-14186 Stockholm, Sweden. [Davis, Mark M.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94304 USA. [Davis, Mark M.] Stanford Univ, Sch Med, Inst Immun Transplantat & Infect, Stanford, CA 94304 USA. [Davis, Mark M.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94304 USA. C1 [Brodin, Petter] Karolinska Inst, Dept Med Solna, Sci Life Lab, S-17165 Stockholm, Sweden. [Brodin, Petter] Karolinska Univ Hosp, Dept Neonatol, S-14186 Stockholm, Sweden. [Davis, Mark M.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94304 USA. [Davis, Mark M.] Stanford Univ, Sch Med, Inst Immun Transplantat & Infect, Stanford, CA 94304 USA. [Davis, Mark M.] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94304 USA. RP Brodin, P (reprint author), Karolinska Inst, Dept Med Solna, Sci Life Lab, S-17165 Stockholm, Sweden.; Brodin, P (reprint author), Karolinska Univ Hosp, Dept Neonatol, S-14186 Stockholm, Sweden. EM petter.brodin@ki.se EM petter.brodin@ki.se RI Brodin, Petter/C-3317-2011 OI Brodin, Petter/0000-0002-8103-0046 FU European Research CouncilEuropean Research Council (ERC); Swedish Research CouncilSwedish Research Council; Swedish Society for Medical Research; Karolinska InstitutetKarolinska Institutet; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19 AI090019, U19 AI057229]; Howard Hughes Medical InstituteHoward Hughes Medical Institute FX P.B. is supported by a starting grant from the European Research Council, the Swedish Research Council, the Swedish Society for Medical Research, and Karolinska Institutet. M.M.D. is supported by NIH grants U19 AI090019, U19 AI057229 and the Howard Hughes Medical Institute. 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Rev. Immunol. PD JAN PY 2017 VL 17 IS 1 BP 21 EP 29 DI 10.1038/nri.2016.125 PG 9 WC Immunology SC Immunology GA EH6TX UT WOS:000391907900009 PM 27916977 OA Green Accepted DA 2020-07-01 ER PT J AU Dodd, D Spitzer, MH Van Treuren, W Merrill, BD Hryckowian, AJ Higginbottom, SK Le, A Cowan, TM Nolan, GP Fischbach, MA Sonnenburg, JL AF Dodd, Dylan Spitzer, Matthew H. Van Treuren, William Merrill, Bryan D. Hryckowian, Andrew J. Higginbottom, Steven K. Le, Anthony Cowan, Tina M. Nolan, Garry P. Fischbach, Michael A. Sonnenburg, Justin L. TI A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites SO NATURE LA English DT Article ID CLOSTRIDIUM-SPOROGENES; MASS CYTOMETRY; PRODUCTS; IMMUNE; BLOOD AB The human gut microbiota produces dozens of metabolites that accumulate in the bloodstream(1,2), where they can have systemic effects on the host. Although these small molecules commonly reach concentrations similar to those achieved by pharmaceutical agents, remarkably little is known about the microbial metabolic pathways that produce them. Here we use a combination of genetics and metabolic profiling to characterize a pathway from the gut symbiont Clostridium sporogenes that generates aromatic amino acid metabolites. Our results reveal that this pathway produces twelve compounds, nine of which are known to accumulate in host serum. All three aromatic amino acids (tryptophan, phenylalanine and tyrosine) serve as substrates for the pathway, and it involves branching and alternative reductases for specific intermediates. By genetically manipulating C. sporogenes, we modulate serum levels of these metabolites in gnotobiotic mice, and show that in turn this affects intestinal permeability and systemic immunity. This work has the potential to provide the basis of a systematic effort to engineer the molecular output of the gut bacterial community. C1 [Dodd, Dylan; Spitzer, Matthew H.; Le, Anthony; Cowan, Tina M.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Dodd, Dylan; Spitzer, Matthew H.; Van Treuren, William; Merrill, Bryan D.; Hryckowian, Andrew J.; Higginbottom, Steven K.; Nolan, Garry P.; Sonnenburg, Justin L.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Fischbach, Michael A.] Univ Calif San Francisco, California Inst Quantitat Biosci, San Francisco, CA 94143 USA. [Fischbach, Michael A.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Spitzer, Matthew H.] Univ Calif San Francisco, Parker Inst Canc Immunotherapy, Helen Diller Family Comprehens Canc Ctr, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Fischbach, Michael A.] Stanford Univ, Dept Bioengn & ChEM H, Stanford, CA 94305 USA. C1 [Dodd, Dylan; Spitzer, Matthew H.; Le, Anthony; Cowan, Tina M.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Dodd, Dylan; Spitzer, Matthew H.; Van Treuren, William; Merrill, Bryan D.; Hryckowian, Andrew J.; Higginbottom, Steven K.; Nolan, Garry P.; Sonnenburg, Justin L.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Fischbach, Michael A.] Univ Calif San Francisco, California Inst Quantitat Biosci, San Francisco, CA 94143 USA. [Fischbach, Michael A.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Spitzer, Matthew H.] Univ Calif San Francisco, Parker Inst Canc Immunotherapy, Helen Diller Family Comprehens Canc Ctr, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Fischbach, Michael A.] Stanford Univ, Dept Bioengn & ChEM H, Stanford, CA 94305 USA. RP Sonnenburg, JL (reprint author), Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA.; Fischbach, MA (reprint author), Univ Calif San Francisco, California Inst Quantitat Biosci, San Francisco, CA 94143 USA.; Fischbach, MA (reprint author), Stanford Univ, Dept Bioengn & ChEM H, Stanford, CA 94305 USA. EM fischbach@fischbachgroup.org; jsonnenburg@stanford.edu EM fischbach@fischbachgroup.org; jsonnenburg@stanford.edu RI Nolan, Garry/AAE-7903-2019; Merrill, Bryan/L-1235-2015 OI Merrill, Bryan/0000-0002-9967-5539; Fischbach, Michael/0000-0003-3079-8247; Spitzer, Matthew/0000-0002-5291-3819 FU National Institutes of Health NIDDKUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01-DK101674]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DP2-OD006515, U19AI057229, U19AI100627, R33CA183654, R33CA0183692, R01GM10983601, R01CA184968, R01CA19665701, R21CA183660, R01NS08953301, 5UH2AR067676, R01HL120724, DP5-OD023056]; FDAUnited States Department of Health & Human Services [BAA-12-00118]; Department of Defence [OC110674, W81XWH-14-1-0 180]; Gates FoundationGates Foundation [OPP1113682, DP1 DK113598, R01 DK110174]; HHMI-Simons Faculty Scholars Award; Byers Award in Basic Science; David and Lucile Packard FoundationThe David & Lucile Packard Foundation; BASF research grant; Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Awards; NIH postdoctoral NRSA [T32-AI007328]; National Science FoundationNational Science Foundation (NSF) [DGE-114747] FX We thank A. I. Scott for technical assistance and S. Yoshida (Kyoto University) for critical review of the manuscript. This work was funded by a grant from the National Institutes of Health NIDDK (R01-DK101674) to J.L.S. and M.A.F., an NIH Director's New Innovator Award (DP2-OD006515) to J.L.S., and Early Independence Award (DP5-OD023056) to M.H.S., FDA Grant BAA-12-00118 to G.P.N., NIH Awards U19AI057229, U19AI100627, R33CA183654, R33CA0183692, R01GM10983601, R01CA184968, R01CA19665701, R21CA183660, R01NS08953301, 5UH2AR067676 and R01HL120724 to G.P.N., Department of Defence Grants OC110674 and W81XWH-14-1-0 180 to G.P.N., Gates Foundation Grant OPP1113682 to G.P.N., DP1 DK113598 to M.A.F., R01 DK110174 to M.A.F., HHMI-Simons Faculty Scholars Award to M.A.F., Byers Award in Basic Science to M.A.F., a Fellowship for Science and Engineering from the David and Lucile Packard Foundation to M.A.F. and a BASF research grant to M.A.F, and two Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Awards to M.A.F. and J.L.S. A.J.H. was supported by an NIH postdoctoral NRSA (T32-AI007328). W.V.T. and B.D.M. were each supported by a National Science Foundation Graduate Research Fellowship Grant No. DGE-114747. 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Knell, Jamie Goldrath, Ananda Jojic, Vladimir Koller, Daphne Shay, Tal Regev, Aviv Cohen, Nadia Brennan, Patrick Brenner, Michael Kim, Francis Rao, Tata Nageswara Wagers, Amy Heng, Tracy Ericson, Jeffrey Rothamel, Katherine Ortiz-Lopez, Adriana Mathis, Diane Bezman, Natalie A. Sun, Joseph C. Min-Oo, Gundula Kim, Charlie C. Lanier, Lewis L. Miller, Jennifer Brown, Brian Merad, Miriam Gautier, Emmanuel L. Jakubzick, Claudia Randolph, Gwendalyn J. Monach, Paul Blair, David A. Dustin, Michael L. Shinton, Susan A. Hardy, Richard R. Laidlaw, David Collins, Jim Gazit, Roi Rossi, Derrick J. Malhotra, Nidhi Sylvia, Katelyn Kang, Joonsoo Kreslavsky, Taras Fletcher, Anne Elpek, Kutlu Bellemare-Pelletier, Angelique Malhotra, Deepali Turley, Shannon CA Immunological Genome Consortium TI The transcriptional landscape of alpha beta T cell differentiation SO NATURE IMMUNOLOGY LA English DT Article ID NEGATIVE SELECTION; POSITIVE SELECTION; GENE-EXPRESSION; PRE-TCR; C-MYC; CLONAL DELETION; LYMPHOCYTE DEVELOPMENT; INDUCED PROLIFERATION; THYMOCYTE SELECTION; CENTRAL TOLERANCE AB The differentiation of abT cells from thymic precursors is a complex process essential for adaptive immunity. Here we exploited the breadth of expression data sets from the Immunological Genome Project to analyze how the differentiation of thymic precursors gives rise to mature T cell transcriptomes. We found that early T cell commitment was driven by unexpectedly gradual changes. In contrast, transit through the CD4(+)CD8(+) stage involved a global shutdown of housekeeping genes that is rare among cells of the immune system and correlated tightly with expression of the transcription factor c-Myc. Selection driven by major histocompatibility complex (MHC) molecules promoted a large-scale transcriptional reactivation. We identified distinct signatures that marked cells destined for positive selection versus apoptotic deletion. Differences in the expression of unexpectedly few genes accompanied commitment to the CD4(+) or CD8(+) lineage, a similarity that carried through to peripheral T cells and their activation, demonstrated by mass cytometry phosphoproteomics. The transcripts newly identified as encoding candidate mediators of key transitions help define the 'known unknowns' of thymocyte differentiation. C1 [Mingueneau, Michael; Cruse, Richard; Ericson, Jeffrey; Mathis, Diane; Benoist, Christophe; Heng, Tracy; Ericson, Jeffrey; Rothamel, Katherine; Ortiz-Lopez, Adriana; Mathis, Diane] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Div Immunol, Boston, MA 02115 USA. [Kreslavsky, Taras; Kobayashi, Koichi; von Boehmer, Harald; Kreslavsky, Taras; Fletcher, Anne; Elpek, Kutlu; Bellemare-Pelletier, Angelique; Malhotra, Deepali; Turley, Shannon] Dana Farber Canc Inst, Boston, MA USA. [Gray, Daniel] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia. [Gray, Daniel] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Mol Genet Canc Div, Parkville, Vic 3050, Australia. [Gray, Daniel] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Div Immunol, Parkville, Vic 3050, Australia. [Heng, Tracy] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic, Australia. [Bendall, Sean; Spitzer, Matt; Nolan, Garry] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Palo Alto, CA 94304 USA. [Kobayashi, Koichi] Texas A&M Hlth Sci Ctr, Dept Microbial & Mol Pathogenesis, College Stn, TX USA. [Best, Adam J.; Knell, Jamie; Goldrath, Ananda] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Jojic, Vladimir; Koller, Daphne] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Shay, Tal; Regev, Aviv] MIT, Broad Inst, Cambridge, MA 02139 USA. [Shay, Tal; Regev, Aviv] MIT, Dept Biol, Cambridge, MA USA. [Cohen, Nadia; Brennan, Patrick; Brenner, Michael] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Kim, Francis; Rao, Tata Nageswara; Wagers, Amy] Joslin Diabet Ctr, Boston, MA 02215 USA. [Bezman, Natalie A.; Sun, Joseph C.; Min-Oo, Gundula; Kim, Charlie C.; Lanier, Lewis L.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Miller, Jennifer; Brown, Brian; Merad, Miriam; Gautier, Emmanuel L.; Jakubzick, Claudia; Randolph, Gwendalyn J.] Mt Sinai Hosp, Icahn Med Inst, New York, NY 10029 USA. [Gautier, Emmanuel L.; Randolph, Gwendalyn J.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Monach, Paul] Boston Univ, Dept Med, Boston, MA 02215 USA. [Blair, David A.; Dustin, Michael L.] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY USA. [Shinton, Susan A.; Hardy, Richard R.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Laidlaw, David] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Collins, Jim] Boston Univ, Howard Hughes Med Inst, Dept Biomed Engn, Boston, MA 02215 USA. [Gazit, Roi; Rossi, Derrick J.] Childrens Hosp, Program Mol Med, Boston, MA 02115 USA. [Malhotra, Nidhi; Sylvia, Katelyn; Kang, Joonsoo] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. [Kreslavsky, Taras; Fletcher, Anne; Elpek, Kutlu; Bellemare-Pelletier, Angelique; Malhotra, Deepali; Turley, Shannon] Harvard Univ, Sch Med, Boston, MA USA. C1 [Mingueneau, Michael; Cruse, Richard; Ericson, Jeffrey; Mathis, Diane; Benoist, Christophe; Heng, Tracy; Ericson, Jeffrey; Rothamel, Katherine; Ortiz-Lopez, Adriana; Mathis, Diane] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Div Immunol, Boston, MA 02115 USA. [Kreslavsky, Taras; Kobayashi, Koichi; von Boehmer, Harald; Kreslavsky, Taras; Fletcher, Anne; Elpek, Kutlu; Bellemare-Pelletier, Angelique; Malhotra, Deepali; Turley, Shannon] Dana Farber Canc Inst, Boston, MA USA. [Gray, Daniel] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia. [Gray, Daniel] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Mol Genet Canc Div, Parkville, Vic 3050, Australia. [Gray, Daniel] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Div Immunol, Parkville, Vic 3050, Australia. [Heng, Tracy] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic, Australia. [Bendall, Sean; Spitzer, Matt; Nolan, Garry] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Palo Alto, CA 94304 USA. [Kobayashi, Koichi] Texas A&M Hlth Sci Ctr, Dept Microbial & Mol Pathogenesis, College Stn, TX USA. [Best, Adam J.; Knell, Jamie; Goldrath, Ananda] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Jojic, Vladimir; Koller, Daphne] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Shay, Tal; Regev, Aviv] MIT, Broad Inst, Cambridge, MA 02139 USA. [Shay, Tal; Regev, Aviv] MIT, Dept Biol, Cambridge, MA USA. [Cohen, Nadia; Brennan, Patrick; Brenner, Michael] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Kim, Francis; Rao, Tata Nageswara; Wagers, Amy] Joslin Diabet Ctr, Boston, MA 02215 USA. [Bezman, Natalie A.; Sun, Joseph C.; Min-Oo, Gundula; Kim, Charlie C.; Lanier, Lewis L.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Miller, Jennifer; Brown, Brian; Merad, Miriam; Gautier, Emmanuel L.; Jakubzick, Claudia; Randolph, Gwendalyn J.] Mt Sinai Hosp, Icahn Med Inst, New York, NY 10029 USA. [Gautier, Emmanuel L.; Randolph, Gwendalyn J.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Monach, Paul] Boston Univ, Dept Med, Boston, MA 02215 USA. [Blair, David A.; Dustin, Michael L.] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY USA. [Shinton, Susan A.; Hardy, Richard R.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Laidlaw, David] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Collins, Jim] Boston Univ, Howard Hughes Med Inst, Dept Biomed Engn, Boston, MA 02215 USA. [Gazit, Roi; Rossi, Derrick J.] Childrens Hosp, Program Mol Med, Boston, MA 02115 USA. [Malhotra, Nidhi; Sylvia, Katelyn; Kang, Joonsoo] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. [Kreslavsky, Taras; Fletcher, Anne; Elpek, Kutlu; Bellemare-Pelletier, Angelique; Malhotra, Deepali; Turley, Shannon] Harvard Univ, Sch Med, Boston, MA USA. RP Benoist, C (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunol, Div Immunol, Boston, MA 02115 USA. EM cbdm@hms.harvard.edu; cbdm@hms.harvard.edu EM cbdm@hms.harvard.edu; cbdm@hms.harvard.edu RI Heng, Tracy/B-9847-2015; Nolan, Garry/AAE-7903-2019; Lanier, Lewis L/E-2139-2014; Mingueneau, Michael/O-5313-2019; Gazit, Roi/J-3352-2017; Dustin, Michael/AAM-4611-2020; Gray, Daniel HD/A-3293-2013; Gautier, Emmanuel L./E-2259-2017; Laidlaw, David/M-4686-2019 OI Heng, Tracy/0000-0003-4147-8986; Lanier, Lewis L/0000-0003-1308-3952; Mingueneau, Michael/0000-0002-3873-7329; Gray, Daniel HD/0000-0002-8457-8242; Gautier, Emmanuel L./0000-0003-2976-7566; Monach, Paul/0000-0003-4937-0515; Spitzer, Matthew/0000-0002-5291-3819; Dustin, Michael/0000-0003-4983-6389; Kreslavsky, Taras/0000-0002-6672-1914; Fletcher, Anne/0000-0003-1534-1142; Kim, Charles/0000-0001-6474-8227; kang, joonsoo/0000-0001-8419-7995; Miller, Jennifer/0000-0002-3591-369X; Gazit, Roi/0000-0002-0548-2147; Tata, Nageswara Rao/0000-0002-9928-5944; Malhotra, Deepali/0000-0002-8215-7639 FU US National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI072073]; Human Frontier Science ProgramHuman Frontier Science Program [HFSP-LT000096]; National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [637353]; Australian Research CouncilAustralian Research Council [LP110201169] FX We thank K. Hattori, A. Ortiz-Lopez and N. Asinovski for technical assistance with mice and antibodies; J. Moore and A. Kressler for flow cytometry; and C. Laplace for assistance with figure preparation. Supported by the US National Institutes of Health (AI072073), the Human Frontier Science Program (HFSP-LT000096 to M. M.), the National Health and Medical Research Council (637353 to D.G.) and the Australian Research Council (LP110201169 to, T.H.). 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Immunol. PD JUN PY 2013 VL 14 IS 6 BP 619 EP + DI 10.1038/ni.2590 PG 16 WC Immunology SC Immunology GA 146RG UT WOS:000319107600015 PM 23644507 OA Green Accepted DA 2020-07-01 ER PT J AU Shekhar, K Brodin, P Davis, MM Chakraborty, AK AF Shekhar, Karthik Brodin, Petter Davis, Mark M. Chakraborty, Arup K. TI Automatic Classification of Cellular Expression by Nonlinear Stochastic Embedding (ACCENSE) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunophenotyping; machine learning; class discovery; CyTOF; FACS ID FLOW-CYTOMETRY DATA; T-CELLS; MEMORY; EFFECTOR; HOMEOSTASIS; LYMPHOCYTES; IMMUNE; CD4(+); GUIDE AB Mass cytometry enables an unprecedented number of parameters to be measured in individual cells at a high throughput, but the large dimensionality of the resulting data severely limits approaches relying on manual "gating." Clustering cells based on phenotypic similarity comes at a loss of single-cell resolution and often the number of subpopulations is unknown a priori. Here we describe ACCENSE, a tool that combines nonlinear dimensionality reduction with density-based partitioning, and displays multivariate cellular phenotypes on a 2D plot. We apply ACCENSE to 35-parameter mass cytometry data from CD8(+) T cells derived from specific pathogen-free and germ-free mice, and stratify cells into phenotypic subpopulations. Our results show significant heterogeneity within the known CD8(+) T-cell subpopulations, and of particular note is that we find a large novel subpopulation in both specific pathogen-free and germ-free mice that has not been described previously. This subpopulation possesses a phenotypic signature that is distinct from conventional naive and memory subpopulations when analyzed by ACCENSE, but is not distinguishable on a biaxial plot of standard markers. We are able to automatically identify cellular subpopulations based on all proteins analyzed, thus aiding the full utilization of powerful new single-cell technologies such as mass cytometry. C1 [Shekhar, Karthik] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Shekhar, Karthik; Chakraborty, Arup K.] Ragon Inst MGH MIT & Harvard, Boston, MA 02129 USA. [Brodin, Petter; Davis, Mark M.] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Stanford, CA 94304 USA. [Brodin, Petter; Davis, Mark M.] Stanford Univ, Inst Immun Transplantat & Infect, Sch Med, Stanford, CA 94304 USA. [Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. C1 [Shekhar, Karthik] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Shekhar, Karthik; Chakraborty, Arup K.] Ragon Inst MGH MIT & Harvard, Boston, MA 02129 USA. [Brodin, Petter; Davis, Mark M.] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Stanford, CA 94304 USA. [Brodin, Petter; Davis, Mark M.] Stanford Univ, Inst Immun Transplantat & Infect, Sch Med, Stanford, CA 94304 USA. [Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Davis, MM (reprint author), Stanford Univ, Dept Microbiol & Immunol, Sch Med, Stanford, CA 94304 USA. EM mmdavis@stanford.edu; arupc@mit.edu EM mmdavis@stanford.edu; arupc@mit.edu RI Brodin, Petter/C-3317-2011 OI Brodin, Petter/0000-0002-8103-0046 FU Poitras pre-doctoral fellowship; Ragon Institute of MGH; MIT; Harvard; Wenner-Gren Foundation; Swedish American Foundation [U189 AI 090019]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [PO1 AI091580] FX We are grateful to Dr. G. Berman and Prof. J. Shaevitz for sharing unpublished work, and to Prof. A. Ferguson for a critical reading of the manuscript. We thank Prof. J. Sonnenburg for providing the GF mice. This research was supported by a Poitras pre-doctoral fellowship (K.S.), the Ragon Institute of MGH, MIT and Harvard (K.S. and A.K.C.), the Wenner-Gren Foundation and the Swedish American Foundation (P. B.), U189 AI 090019 (to M.M.D.), and a National Institutes of Health PO1 AI091580 (to A.K.C.). 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Gherardini, Pier Federico TI Highly multiplexed simultaneous detection of RNAs and proteins in single cells SO NATURE METHODS LA English DT Article ID IN-SITU HYBRIDIZATION; FLOW-CYTOMETRY; MESSENGER-RNA; GENE-EXPRESSION; INDIVIDUAL CELLS; PROXIMITY LIGATION; SEQ; HETEROGENEITY; COMPLEXES; LEVEL AB To enable the detection of expression signatures specific to individual cells, we developed PLAYR (proximity ligation assay for RNA), a method for highly multiplexed transcript quantification by flow and mass cytometry that is compatible with standard antibody staining. When used with mass cytometry, PLAYR allowed for the simultaneous quantification of more than 40 different mRNAs and proteins. In primary cells, we quantified multiple transcripts, with the identity and functional state of each analyzed cell defined on the basis of the expression of a separate set of transcripts or proteins. By expanding high-throughput deep phenotyping of cells beyond protein epitopes to include RNA expression, PLAYR opens a new avenue for the characterization of cellular metabolism. C1 [Frei, Andreas P.; Bava, Felice-Alessio; Zunder, Eli R.; Hsieh, Elena W. Y.; Chen, Shih-Yu; Nolan, Garry P.; Gherardini, Pier Federico] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Zunder, Eli R.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA. [Hsieh, Elena W. Y.] Univ Colorado, Dept Pediat, Denver, CO 80202 USA. [Hsieh, Elena W. Y.] Univ Colorado, Dept Immunol & Microbiol, Denver, CO 80202 USA. C1 [Frei, Andreas P.; Bava, Felice-Alessio; Zunder, Eli R.; Hsieh, Elena W. Y.; Chen, Shih-Yu; Nolan, Garry P.; Gherardini, Pier Federico] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Zunder, Eli R.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA. [Hsieh, Elena W. 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EM gnolan@stanford.edu; pfg@stanford.edu EM gnolan@stanford.edu; pfg@stanford.edu RI Chen, Shih-Yu/S-2919-2019; Nolan, Garry/AAE-7903-2019 FU Swiss National Science FoundationSwiss National Science Foundation (SNSF); EMBO Long-Term FellowshipEuropean Molecular Biology Organization (EMBO); Marie Curie International Outgoing FellowshipEuropean Union (EU); Human Frontier Science Program Long-Term FellowshipHuman Frontier Science Program; US National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19 AI057229, 1U19AI100627, R01CA184968, 1R33CA183654-01, R33CA183692, 1R01GM10983601, 1R21CA183660, 1R01NS08953301, OPP1113682, 5UH2AR067676, 1R01CA19665701, R01HL120724]; US Department of Defense Congressionally Directed Medical Research Programs [OC110674, 11491122]; Northrop-Grumman Corporation; Rachford & Carlotta A. Harris Endowed Chair FX We thank L. Lanier (UCSF, San Francisco, California, USA) for providing the NKL cell line, and A. Trejo and A. Jager for technical assistance. A.P.F. is supported by a Fellowship for Prospective Researchers from the Swiss National Science Foundation, an EMBO Long-Term Fellowship and a Marie Curie International Outgoing Fellowship. P.F.G. is a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation. F.-A.B. is supported by a Human Frontier Science Program Long-Term Fellowship. This work was supported by the US National Institutes of Health (grants U19 AI057229, 1U19AI100627, R01CA184968, 1R33CA183654-01, R33CA183692, 1R01GM10983601, 1R21CA183660, 1R01NS08953301, OPP1113682, 5UH2AR067676, 1R01CA19665701 and R01HL120724 to G.P.N.), US Department of Defense Congressionally Directed Medical Research Programs (grants OC110674 and 11491122 to G.P.N.), the Northrop-Grumman Corporation (G.P.N.) and the Rachford & Carlotta A. Harris Endowed Chair (G.P.N.). 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Methods PD MAR PY 2016 VL 13 IS 3 BP 269 EP + DI 10.1038/NMETH.3742 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DF0NU UT WOS:000371036700029 PM 26808670 OA Green Accepted DA 2020-07-01 ER PT J AU Mrdjen, D Pavlovic, A Hartmann, FJ Schreiner, B Utz, SG Leung, BP Lelios, I Heppner, FL Kipnis, J Merkler, D Greter, M Becher, B AF Mrdjen, Dunja Pavlovic, Anto Hartmann, Felix J. Schreiner, Bettina Utz, Sebastian G. Leung, Brian P. Lelios, Iva Heppner, Frank L. Kipnis, Jonathan Merkler, Doron Greter, Melanie Becher, Burkhard TI High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease SO IMMUNITY LA English DT Article ID TISSUE-RESIDENT MACROPHAGES; ALZHEIMERS-DISEASE; DENDRITIC CELLS; MASS CYTOMETRY; CHOROID-PLEXUS; GM-CSF; MULTIPLE-SCLEROSIS; STEM-CELLS; T-CELLS; MICROGLIA AB Individual reports suggest that the central nervous system (CNS) contains multiple immune cell types with diverse roles in tissue homeostasis, immune defense, and neurological diseases. It has been challenging to map leukocytes across the entire brain, and in particular in pathology, where phenotypic changes and influx of blood-derived cells prevent a clear distinction between reactive leukocyte populations. Here, we applied high-dimensional single-cell mass and fluorescence cytometry, in parallel with genetic fate mapping systems, to identify, locate, and characterize multiple distinct immune populations within the mammalian CNS. Using this approach, we revealed that microglia, several subsets of border-associated macrophages and dendritic cells coexist in the CNS at steady state and exhibit disease-specific transformations in the immune microenvironment during aging and in models of Alzheimer's disease and multiple sclerosis. Together, these data and the described framework provide a resource for the study of disease mechanisms, potential biomarkers, and therapeutic targets in CNS disease. C1 [Mrdjen, Dunja; Pavlovic, Anto; Hartmann, Felix J.; Schreiner, Bettina; Utz, Sebastian G.; Leung, Brian P.; Lelios, Iva; Greter, Melanie; Becher, Burkhard] Univ Zurich, Inst Expt Immunol, Zurich, Switzerland. [Heppner, Frank L.] Charite Univ Med Berlin, Dept Neuropathol, Berlin, Germany. [Kipnis, Jonathan] Univ Virginia, Ctr Brain Immunol & Glia, Dept Neurosci, Charlottesville, VA USA. [Merkler, Doron] Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland. [Merkler, Doron] Geneva Univ Hosp, Div Clin Pathol, Geneva, Switzerland. C1 [Mrdjen, Dunja; Pavlovic, Anto; Hartmann, Felix J.; Schreiner, Bettina; Utz, Sebastian G.; Leung, Brian P.; Lelios, Iva; Greter, Melanie; Becher, Burkhard] Univ Zurich, Inst Expt Immunol, Zurich, Switzerland. [Heppner, Frank L.] Charite Univ Med Berlin, Dept Neuropathol, Berlin, Germany. [Kipnis, Jonathan] Univ Virginia, Ctr Brain Immunol & Glia, Dept Neurosci, Charlottesville, VA USA. [Merkler, Doron] Univ Geneva, Dept Pathol & Immunol, Geneva, Switzerland. [Merkler, Doron] Geneva Univ Hosp, Div Clin Pathol, Geneva, Switzerland. RP Becher, B (reprint author), Univ Zurich, Inst Expt Immunol, Zurich, Switzerland. EM becher@immunology.uzh.ch EM becher@immunology.uzh.ch OI Heppner, Frank/0000-0001-9816-8917; Greter, Melanie/0000-0002-7220-5369 FU Swiss national science foundationSwiss National Science Foundation (SNSF) [PP00P3_144781, 310030_146130, 316030_150768, 310030_170320]; European Union: FP7 ITN_NeuroKine; European Union: FP7 Project ATECT; University Priority Project Translational Cancer Research; National Science Foundation Graduate Research Fellowship ProgramNational Science Foundation (NSF) [DGE1418060]; Forschungskredit - University of Zurich FX We thank the Mass- and Flow Cytometry Facility (University of Zurich) and the Center for Microscopy and Image Analysis (University of Zurich) for technical assistance; Lucy Robinson of Insight Editing London for critical review and editing of the manuscript; Nathalie Krakoski for discussions about BAMs; Nikolaus Deigendesch for APP/PS1 mouse transfers; Nir Yogev and Andrea Cogurra for discussions about all things meningeal; Will Macnair for comparison of protein and RNA expression; and Sarah Mundt for critical review and editing of the manuscript. This work was supported by grants from the Swiss national science foundation (PP00P3_144781 to M.G., 310030_146130, 316030_150768, 310030_170320 to B.B.), from the European Union: FP7 ITN_NeuroKine (B.B.) and FP7 Project ATECT (B.B.), from the University Priority Project Translational Cancer Research (B.B.), from the National Science Foundation Graduate Research Fellowship Program (DGE1418060) (B.P.L.), and the Forschungskredit awarded by the University of Zurich to D. Mrdjen. 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and cytotoxic T cells and by releasing different types of cytokines in tissues to mediate protection against a wide range of pathogenic microorganisms. 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TI Mass spectrometry imaging and profiling of single cells SO JOURNAL OF PROTEOMICS LA English DT Review DE Secondary ion mass spectrometry; Matrix assisted laser desorption/ionization; Subcellular profiling; Elemental imaging; Mass cytometry; Tissue imaging ID LASER-DESORPTION IONIZATION; PRIMARY ION-BOMBARDMENT; LA-ICP-MS; SECONDARY-ION; TOF-SIMS; MALDI-MS; CHEMICAL-COMPOSITION; SAMPLE PREPARATION; TUMOR-CELLS; RELATIVE QUANTIFICATION AB Mass spectrometry imaging and profiling of individual cells and subcellular structures provide unique analytical capabilities for biological and biomedical research, including determination of the biochemical heterogeneity of cellular populations and intracellular localization of pharmaceuticals. Two mass spectrometry technologies-secondary ion mass spectrometry (SIMS) and matrix assisted laser desorption/ionization mass spectrometry (MALDI MS)-are most often used in micro-bioanalytical investigations. Recent advances in ion probe technologies have increased the dynamic range and sensitivity of analyte detection by SIMS, allowing two- and three-dimensional localization of analytes in a variety of cells. SIMS operating in the mass spectrometry imaging (MSI) mode can routinely reach spatial resolutions at the submicron level; therefore, it is frequently used in studies of the chemical composition of subcellular structures. MALDI MS offers a large mass range and high sensitivity of analyte detection. It has been successfully applied in a variety of single-cell and organelle profiling studies. Innovative instrumentation such as scanning microprobe MALDI and mass microscope spectrometers enables new subcellular MSI measurements. Other approaches for MS-based chemical imaging and profiling include those based on near-field laser ablation and inductively-coupled plasma MS analysis, which offer complementary capabilities for subcellular chemical imaging and profiling. This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User's Guide to a New Technique for Biological and Biomedical Research. (C) 2012 Elsevier B.V. All rights reserved. C1 [Sweedler, Jonathan V.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. Univ Illinois, Beckman Inst Sci & Technol, Urbana, IL 61801 USA. C1 [Sweedler, Jonathan V.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. Univ Illinois, Beckman Inst Sci & Technol, Urbana, IL 61801 USA. RP Sweedler, JV (reprint author), Univ Illinois, Dept Chem, 1209 W Calif St, Urbana, IL 61801 USA. EM jsweedle@illinois.edu EM jsweedle@illinois.edu RI Rubakhin, Stanislav S/E-6685-2017; Sweedler, Jonathan V/A-9405-2009 OI Rubakhin, Stanislav S/0000-0003-0437-1493; Sweedler, Jonathan V/0000-0003-3107-9922 FU National Institute on Drug Abuse (NIDA)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [P30 DA018310]; Department of EnergyUnited States Department of Energy (DOE) [DE-SC0006642] FX This work was supported by Award No. P30 DA018310 from the National Institute on Drug Abuse (NIDA) and the Department of Energy by Award No. DE-SC0006642. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. We also thank Stephanie Baker for assistance with manuscript preparation and reviewers for helpful feedback. The authors declare they have no conflicts of interest. 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Proteomics PD AUG 30 PY 2012 VL 75 IS 16 SI SI BP 5036 EP 5051 DI 10.1016/j.jprot.2012.03.017 PG 16 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 002ID UT WOS:000308524400014 PM 22498881 OA Green Accepted DA 2020-07-01 ER PT J AU Spitzer, MH Gherardini, PF Fragiadakis, GK Bhattacharya, N Yuan, RT Hotson, AN Finck, R Carmi, Y Zunder, ER Fantl, WJ Bendall, SC Engleman, EG Nolan, GP AF Spitzer, Matthew H. Gherardini, Pier Federico Fragiadakis, Gabriela K. Bhattacharya, Nupur Yuan, Robert T. Hotson, Andrew N. Finck, Rachel Carmi, Yaron Zunder, Eli R. Fantl, Wendy J. Bendall, Sean C. Engleman, Edgar G. Nolan, Garry P. TI An interactive reference framework for modeling a dynamic immune system SO SCIENCE LA English DT Article ID MASS CYTOMETRY; GENE-EXPRESSION; T-CELLS; MOUSE; NETWORK; IDENTIFICATION; PROGRESSION; VISUALIZATION; BIOLOGY; GAMMA AB Immune cells function in an interacting hierarchy that coordinates the activities of various cell types according to genetic and environmental contexts. We developed graphical approaches to construct an extensible immune reference map from mass cytometry data of cells from different organs, incorporating landmark cell populations as flags on the map to compare cells from distinct samples. The maps recapitulated canonical cellular phenotypes and revealed reproducible, tissue-specific deviations. The approach revealed influences of genetic variation and circadian rhythms on immune system structure, enabled direct comparisons of murine and human blood cell phenotypes, and even enabled archival fluorescence-based flow cytometry data to be mapped onto the reference framework. This foundational reference map provides a working definition of systemic immune organization to which new data can be integrated to reveal deviations driven by genetics, environment, or pathology. C1 [Spitzer, Matthew H.; Gherardini, Pier Federico; Fragiadakis, Gabriela K.; Hotson, Andrew N.; Finck, Rachel; Zunder, Eli R.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Spitzer, Matthew H.; Bhattacharya, Nupur; Yuan, Robert T.; Carmi, Yaron; Bendall, Sean C.; Engleman, Edgar G.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Spitzer, Matthew H.; Yuan, Robert T.; Bendall, Sean C.; Engleman, Edgar G.; Nolan, Garry P.] Stanford Univ, Program Immunol, Stanford, CA 94305 USA. [Fantl, Wendy J.] Stanford Univ, Dept Obstet & Gynecol, Div Gynecol Oncol, Stanford, CA 94305 USA. C1 [Spitzer, Matthew H.; Gherardini, Pier Federico; Fragiadakis, Gabriela K.; Hotson, Andrew N.; Finck, Rachel; Zunder, Eli R.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Spitzer, Matthew H.; Bhattacharya, Nupur; Yuan, Robert T.; Carmi, Yaron; Bendall, Sean C.; Engleman, Edgar G.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Spitzer, Matthew H.; Yuan, Robert T.; Bendall, Sean C.; Engleman, Edgar G.; Nolan, Garry P.] Stanford Univ, Program Immunol, Stanford, CA 94305 USA. [Fantl, Wendy J.] Stanford Univ, Dept Obstet & Gynecol, Div Gynecol Oncol, Stanford, CA 94305 USA. RP Spitzer, MH (reprint author), Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. EM matthew.spitzer@stanford.edu; gnolan@stanford.edu EM matthew.spitzer@stanford.edu; gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019 OI Spitzer, Matthew/0000-0002-5291-3819 FU Fluidigm Sciences; George D. Smith Stanford graduate fellowship; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [F31CA189331, T32GM007276, NRSA F32 GM093508-01, K99GM104148-01, 1U19AI100627, 1R01GM109836, 7500108142]; Stanford Bio-X graduate fellowship; CIRM Basic Biology II [RB2-01592]; Damon Runyon Cancer Research Foundation [DRG-2017-09]; NIAIDUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [HHSN272201200028C, PN2EY018228 0158 G KB065, 1R01CA130826]; DODUnited States Department of Defense [OC110674, 11491122]; Bill and Melinda Gates FoundationGates Foundation [OPP1113682]; CIRMCalifornia Institute for Regenerative Medicine [RB2-01592, DR1-01477]; FDAUnited States Department of Health & Human Services [HHSF223201210194C BAA-12-00118]; European CommissionEuropean Commission Joint Research Centre [HEALTH.2010.1.2-1]; Rachford and Carlota A. Harris endowed professorship; The NIAID [5U54CA143907NIH, HHSN272200700038C, N01-HV-00242, 41000411217, 5-24927, P01 CA034233-22A1, RFA CA 09-009, RFA CA 09-011, U19 AI057229, U54CA149145, 5R01AI073724, R01CA184968, R33 CA183654, R33 CA183692, 1R01NS089533, 201303028] FX All mass cytometry data are accessible at www.cytobank.org/nolanlab/reports and the. R package is available at https://github.com/nolanlab. R. Finck, S. Bendall, and G.P.N. have served as paid consultants of Fluidigm Sciences, the maker of the mass cytometry instrumentation and reagents used for the data collection in this study. We thank J. Kenkel, B. Burt, D.-H. Wang, and M. Ch'ng for their assistance in tissue processing; A. Trejo and A. Jager for mass cytometry quality control and maintenance; B. Gaudilliere and M. Angst for access to human whole blood data; and M. Angelo, C. Loh, N. Reticker-Flynn, and L. Sanman for constructive feedback. Supported by a George D. Smith Stanford graduate fellowship and NIH grant F31CA189331 (M.H.S.); a Stanford Bio-X graduate fellowship and NIH grant T32GM007276 (G.K.F.); CIRM Basic Biology II RB2-01592 and NIH grant NRSA F32 GM093508-01 (E.R.Z.); Damon Runyon Cancer Research Foundation fellowship DRG-2017-09 and NIH grant K99GM104148-01 (S. C. B.); NIH grants 1U19AI100627, 1R01GM109836, and 7500108142, NIAID Bioinformatics Support Contract HHSN272201200028C, PN2EY018228 0158 G KB065, 1R01CA130826, 5U54CA143907NIH, HHSN272200700038C, N01-HV-00242, 41000411217, 5-24927, P01 CA034233-22A1, RFA CA 09-009, RFA CA 09-011, U19 AI057229, U54CA149145, 5R01AI073724, R01CA184968, R33 CA183654, R33 CA183692, 1R01NS089533, 201303028; DOD grants OC110674 and 11491122; Bill and Melinda Gates Foundation grant OPP1113682; CIRM grants DR1-01477 and RB2-01592; FDA grant HHSF223201210194C BAA-12-00118; European Commission grant HEALTH.2010.1.2-1; and the Rachford and Carlota A. Harris endowed professorship (G.P.N.).. P.F.G. is a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation. 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Marr, Carsten Buettner, Florian TI destiny: diffusion maps for large-scale single cell data in R SO BIOINFORMATICS LA English DT Article AB Diffusion maps are a spectral method for non-linear dimension reduction and have recently been adapted for the visualization of single-cell expression data. Here we present destiny, an efficient R implementation of the diffusion map algorithm. Our package includes a single-cell specific noise model allowing for missing and censored values. In contrast to previous implementations, we further present an efficient nearest-neighbour approximation that allows for the processing of hundreds of thousands of cells and a functionality for projecting new data on existing diffusion maps. We exemplarily apply destiny to a recent time-resolved mass cytometry dataset of cellular reprogramming. C1 [Angerer, Philipp; Haghverdi, Laleh; Buettner, Maren; Theis, Fabian J.; Marr, Carsten; Buettner, Florian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Computat Biol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. [Theis, Fabian J.] Tech Univ Munich, Ctr Math, Chair Math Modeling Biol Syst, Boltzmannstr 3, D-85748 Garching, Germany. C1 [Angerer, Philipp; Haghverdi, Laleh; Buettner, Maren; Theis, Fabian J.; Marr, Carsten; Buettner, Florian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Computat Biol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. [Theis, Fabian J.] Tech Univ Munich, Ctr Math, Chair Math Modeling Biol Syst, Boltzmannstr 3, D-85748 Garching, Germany. RP Marr, C; Buettner, F (reprint author), Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Computat Biol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. EM carsten.marr@helmholtz-muenchen.de; f.buettner@helmholtz-muenchen.de EM carsten.marr@helmholtz-muenchen.de; f.buettner@helmholtz-muenchen.de RI Marr, Carsten/B-3696-2013; Angerer, Philipp/L-5236-2019 OI Marr, Carsten/0000-0003-2154-4552; Angerer, Philipp/0000-0002-0369-2888; Buttner, Maren/0000-0002-6189-3792; Theis, Fabian/0000-0002-2419-1943; Haghverdi, Laleh/0000-0001-9280-9170; Buettner, Florian/0000-0001-5587-6761 FU UK Medical Research CouncilMedical Research Council UK (MRC); Bavarian Research Network for Molecular Biosystems (BioSysNet); ERCEuropean Research Council (ERC); DFG Fellowship through the Graduate School of Quantitative Biosciences Munich (QBM); Medical Research CouncilMedical Research Council UK (MRC) [MR/M01536X/1] FX Supported by the UK Medical Research Council (Career Development Award to FB), the Bavarian Research Network for Molecular Biosystems (BioSysNet) and the ERC (starting grant LatentCauses to FJT). MP, is supported by a DFG Fellowship through the Graduate School of Quantitative Biosciences Munich (QBM). CR Buettner F, 2012, BIOINFORMATICS, V28, pI626, DOI 10.1093/bioinformatics/bts385 Coifman RR, 2008, MULTISCALE MODEL SIM, V7, P842, DOI 10.1137/070696325 Coifman RR, 2005, P NATL ACAD SCI USA, V102, P7426, DOI 10.1073/pnas.0500334102 Haghverdi L, 2015, BIOINFORMATICS, V31, P2989, DOI 10.1093/bioinformatics/btv325 Richards J., 2014, DIFFUSIONMAP DIFFUSI Roditi LD, 2015, CURR OPIN BIOTECH, V34, P9, DOI 10.1016/j.copbio.2014.10.010 Zunder ER, 2015, CELL STEM CELL, V16, P323, DOI 10.1016/j.stem.2015.01.015 NR 7 TC 114 Z9 113 U1 4 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD APR 15 PY 2016 VL 32 IS 8 BP 1241 EP 1243 DI 10.1093/bioinformatics/btv715 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA DJ8QJ UT WOS:000374476800023 PM 26668002 OA Bronze, Green Published DA 2020-07-01 ER PT J AU Lin, JR Fallahi-Sichani, M Sorger, PK AF Lin, Jia-Ren Fallahi-Sichani, Mohammad Sorger, Peter K. TI Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method SO NATURE COMMUNICATIONS LA English DT Article ID TYRAMIDE SIGNAL AMPLIFICATION; PRIMARY ANTIBODIES; IMMUNOHISTOCHEMISTRY; VISUALIZATION; HETEROGENEITY; POPULATIONS; RESPONSES; REVEALS AB Single-cell analysis reveals aspects of cellular physiology not evident from population-based studies, particularly in the case of highly multiplexed methods such as mass cytometry (CyTOF) able to correlate the levels of multiple signalling, differentiation and cell fate markers. Immunofluorescence (IF) microscopy adds information on cell morphology and the microenvironment that are not obtained using flow-based techniques, but the multiplicity of conventional IF is limited. This has motivated development of imaging methods that require specialized instrumentation, exotic reagents or proprietary protocols that are difficult to reproduce in most laboratories. Here we report a public-domain method for achieving high multiplicity single-cell IF using cyclic immunofluorescence (CycIF), a simple and versatile procedure in which four-colour staining alternates with chemical inactivation of fluorophores to progressively build a multichannel image. Because CycIF uses standard reagents and instrumentation and is no more expensive than conventional IF, it is suitable for high-throughput assays and screening applications. C1 [Lin, Jia-Ren; Sorger, Peter K.] Harvard Univ, Sch Med, HMS LINCS Ctr, Boston, MA 02115 USA. [Lin, Jia-Ren; Sorger, Peter K.] Harvard Univ, Sch Med, Lab Syst Pharmacol, Boston, MA 02115 USA. [Fallahi-Sichani, Mohammad; Sorger, Peter K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. C1 [Lin, Jia-Ren; Sorger, Peter K.] Harvard Univ, Sch Med, HMS LINCS Ctr, Boston, MA 02115 USA. [Lin, Jia-Ren; Sorger, Peter K.] Harvard Univ, Sch Med, Lab Syst Pharmacol, Boston, MA 02115 USA. [Fallahi-Sichani, Mohammad; Sorger, Peter K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Sorger, PK (reprint author), Harvard Univ, Sch Med, HMS LINCS Ctr, Boston, MA 02115 USA. EM peter_sorger@hms.harvard.edu EM peter_sorger@hms.harvard.edu OI Sorger, Peter/0000-0002-3364-1838 FU NIH LINCS grant [U54-HL127365] FX We thank J. Albeck and S. Sampattavanich for the FOXO-GFP reporter, GE for early access to a CyTell imaging system and E. Williams for the CycIF web-page. This work was funded by NIH LINCS grant U54-HL127365. M.F. is a Merck Fellow of the Life Sciences Research Foundation. 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TI Single-cell mass cytometry adapted to measurements of the cell cycle SO CYTOMETRY PART A LA English DT Article DE mass cytometry; cell cycle; flow cytometry; retinoblastoma; iododeoxyuridine; hematopoiesis ID HEMATOPOIETIC STEM; HISTONE H3; PROLIFERATION; EXPRESSION; LEUKEMIA AB Mass cytometry is a recently introduced technology that utilizes transition element isotope-tagged antibodies for protein detection on a single-cell basis. By circumventing the limitations of emission spectral overlap associated with fluorochromes utilized in traditional flow cytometry, mass cytometry currently allows measurement of up to 40 parameters per cell. Recently, a comprehensive mass cytometry analysis was described for the hematopoietic differentiation program in human bone marrow from a healthy donor. The current study describes approaches to delineate cell cycle stages utilizing 5-iodo-2-deoxyuridine (IdU) to mark cells in S phase, simultaneously with antibodies against cyclin B1, cyclin A, and phosphorylated histone H3 (S28) that characterize the other cell cycle phases. Protocols were developed in which an antibody against phosphorylated retinoblastoma protein (Rb) at serines 807 and 811 was used to separate cells in G0 and G1 phases of the cell cycle. This mass cytometry method yielded cell cycle distributions of both normal and cancer cell populations that were equivalent to those obtained by traditional fluorescence cytometry techniques. We applied this to map the cell cycle phases of cells spanning the hematopoietic hierarchy in healthy human bone marrow as a prelude to later studies with cancers and other disorders of this lineage. (C) 2012 International Society for Advancement of Cytometry C1 [Behbehani, Gregory K.; Bendall, Sean C.; Clutter, Matthew R.; Fantl, Wendy J.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Behbehani, Gregory K.] Stanford Univ, Sch Med, Div Hematol, Stanford, CA 94305 USA. [Behbehani, Gregory K.] Stanford Univ, Sch Med, Div Oncol, Stanford, CA 94305 USA. C1 [Behbehani, Gregory K.; Bendall, Sean C.; Clutter, Matthew R.; Fantl, Wendy J.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Behbehani, Gregory K.] Stanford Univ, Sch Med, Div Hematol, Stanford, CA 94305 USA. [Behbehani, Gregory K.] Stanford Univ, Sch Med, Div Oncol, Stanford, CA 94305 USA. RP Behbehani, GK (reprint author), 269 Campus Dr,CCSR 3205, Stanford, CA 94305 USA. EM gnolan@stanford.edu EM gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019 FU NIH/NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U19 AI057229, P01 CA034233, HHSN272200700038C, 1R01CA130826, NCI RFA CA 09-011, NHLBI-HV-1005, CIRM DR1-01477, RB2-01592]; European CommissionEuropean Commission Joint Research Centre [HEALTH.2010.1.2-1]; Bill and Melinda Gates FoundationGates Foundation [GF12141-137101]; Rachford and Carlota A. Harris Endowed Professorship; Stanford Cancer Center FX Grant sponsor: NIH/NCI; Grant number: U19 AI057229; Grant number: P01 CA034233; Grant number: HHSN272200700038C; Grant number: 1R01CA130826; Grant number: NCI RFA CA 09-011; Grant number: NHLBI-HV-1005(2); Grant number: CIRM DR1-01477; Grant number: RB2-01592; Grant sponsor: European Commission; Grant number: HEALTH. 2010.1.2-1; Grant sponsor: Bill and Melinda Gates Foundation; Grant number: GF12141-137101; Grant sponsor: Rachford and Carlota A. 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Part A PD JUL PY 2012 VL 81A IS 7 BP 552 EP 566 DI 10.1002/cyto.a.22075 PG 15 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 962PZ UT WOS:000305558700006 PM 22693166 OA Green Accepted DA 2020-07-01 ER PT J AU Fergusson, JR Smith, KE Fleming, VM Rajoriya, N Newell, EW Simmons, R Marchi, E Bjorkander, S Kang, YH Swadling, L Kurioka, A Sahgal, N Lockstone, H Baban, D Freeman, GJ Sverremark-Ekstrom, E Davis, MM Davenport, MP Venturi, V Ussher, JE Willberg, CB Klenerman, P AF Fergusson, Joannah R. Smith, Kira E. Fleming, Vicki M. Rajoriya, Neil Newell, Evan W. Simmons, Ruth Marchi, Emanuele Bjorkander, Sophia Kang, Yu-Hoi Swadling, Leo Kurioka, Ayako Sahgal, Natasha Lockstone, Helen Baban, Dilair Freeman, Gordon J. Sverremark-Ekstrom, Eva Davis, Mark M. Davenport, Miles P. Venturi, Vanessa Ussher, James E. Willberg, Christian B. Klenerman, Paul TI CD161 Defines a Transcriptional and Functional Phenotype across Distinct Human T Cell Lineages SO CELL REPORTS LA English DT Article ID HUMAN NKR-P1A; CUTTING EDGE; EXPRESSION; MAIT; SUBSET; LIGAND; NK; ACTIVATION; PROGRAM; NKRP1A AB The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCR gamma delta+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage. C1 [Fergusson, Joannah R.; Smith, Kira E.; Fleming, Vicki M.; Rajoriya, Neil; Simmons, Ruth; Marchi, Emanuele; Kang, Yu-Hoi; Swadling, Leo; Kurioka, Ayako; Ussher, James E.; Willberg, Christian B.; Klenerman, Paul] Univ Oxford, Peter Medawar Bldg Pathogen Res, Oxford OX1 3SY, England. [Fleming, Vicki M.] Oxford Univ Hosp NHS Trust, Dept Microbiol & Infect Dis, Oxford OX3 9DU, England. [Newell, Evan W.; Davis, Mark M.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Newell, Evan W.] Singapore Immunol Network SIgN, Agcy Sci Technol & Res A STAR, Singapore 138632, Singapore. [Bjorkander, Sophia; Sverremark-Ekstrom, Eva] Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, S-10691 Stockholm, Sweden. [Sahgal, Natasha; Lockstone, Helen; Baban, Dilair] Univ Oxford, Wellcome Trust Ctr Human Genet, Bioinformat & Stat Genet Core, Oxford OX3 7BN, England. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Davenport, Miles P.; Venturi, Vanessa] Prince Wales Hosp, Dept Hematol, Kensington, NSW 2052, Australia. [Ussher, James E.] Univ Otago, Dept Microbiol & Immunol, Dunedin 9054, New Zealand. [Klenerman, Paul] John Radcliffe Hosp, NIHR Oxford Biomed Res Ctr, Oxford OX3 9TU, England. C1 [Fergusson, Joannah R.; Smith, Kira E.; Fleming, Vicki M.; Rajoriya, Neil; Simmons, Ruth; Marchi, Emanuele; Kang, Yu-Hoi; Swadling, Leo; Kurioka, Ayako; Ussher, James E.; Willberg, Christian B.; Klenerman, Paul] Univ Oxford, Peter Medawar Bldg Pathogen Res, Oxford OX1 3SY, England. [Fleming, Vicki M.] Oxford Univ Hosp NHS Trust, Dept Microbiol & Infect Dis, Oxford OX3 9DU, England. [Newell, Evan W.; Davis, Mark M.] Stanford Univ, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Newell, Evan W.] Singapore Immunol Network SIgN, Agcy Sci Technol & Res A STAR, Singapore 138632, Singapore. [Bjorkander, Sophia; Sverremark-Ekstrom, Eva] Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, S-10691 Stockholm, Sweden. [Sahgal, Natasha; Lockstone, Helen; Baban, Dilair] Univ Oxford, Wellcome Trust Ctr Human Genet, Bioinformat & Stat Genet Core, Oxford OX3 7BN, England. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Davenport, Miles P.; Venturi, Vanessa] Prince Wales Hosp, Dept Hematol, Kensington, NSW 2052, Australia. [Ussher, James E.] Univ Otago, Dept Microbiol & Immunol, Dunedin 9054, New Zealand. [Klenerman, Paul] John Radcliffe Hosp, NIHR Oxford Biomed Res Ctr, Oxford OX3 9TU, England. RP Klenerman, P (reprint author), Univ Oxford, Peter Medawar Bldg Pathogen Res, Oxford OX1 3SY, England. EM paul.klenerman@ndm.ox.ac.uk EM paul.klenerman@ndm.ox.ac.uk RI Ussher, James/O-4493-2019; Newell, Evan W/F-9711-2012; Freeman, Gordon/AAC-5380-2019; Sverremark-Ekstrom, Eva/A-2305-2016; Newell, Evan/AAE-9470-2020; Swadling, Leo/Y-5141-2019 OI Ussher, James/0000-0001-9222-7680; Newell, Evan W/0000-0002-2889-243X; Freeman, Gordon/0000-0002-7210-5616; Sverremark-Ekstrom, Eva/0000-0001-6271-8681; Newell, Evan/0000-0002-2889-243X; Swadling, Leo/0000-0002-0537-6715; Davenport, Miles/0000-0002-4751-1831; klenerman, paul/0000-0003-4307-9161; Willberg, Christian/0000-0001-5299-9344; Fergusson, Joannah/0000-0001-9223-1209 FU Wellcome Trust IITM Programme [092871/Z/10/Z]; Wellcome TrustWellcome Trust [WT091663MA]; Medical Research CouncilMedical Research Council UK (MRC); NIHR Biomedical Research Centre (Oxford)National Institute for Health Research (NIHR); Nuffield Department of Clinical Medicine (Oxford); James Martin School for the 21st Century (Oxford); NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIAD U19AI 082630]; Oxford Dominions Trust; National Institute for Health ResearchNational Institute for Health Research (NIHR) [NF-SI-0510-10204] FX The authors would like to thank T. Hansen for the kind provision of the MR1-blocking antibody, N. Rust for sorting expertise, C. Marchant for technical support, and all members of the laboratory for helpful discussion and support. J.R.F is supported by the Wellcome Trust IITM Programme (092871/Z/10/Z). This work was also supported by the Wellcome Trust (WT091663MA), the Medical Research Council, the NIHR Biomedical Research Centre (Oxford), the Nuffield Department of Clinical Medicine (Oxford), the James Martin School for the 21st Century (Oxford), the NIH (NIAD U19AI 082630), and the Oxford Dominions Trust. 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Simonds, Erin F. Fantl, Wendy J. Nolan, Garry P. Bodenmiller, Bernd TI A platinum-based covalent viability reagent for single-cell mass cytometry SO CYTOMETRY PART A LA English DT Article DE mass cytometry; cisplatin; viability reagent ID FLOW-CYTOMETRY; ICP-MS; CISPLATIN; DNA; APOPTOSIS; PHOSPHORYLATION; IDENTIFICATION; SPECTROMETRY; IMMUNOASSAY; SURFACE AB In fluorescence-based flow cytometry, cellular viability is determined with membrane-impermeable fluorescent reagents that specifically enter and label plasma membrane-compromised nonviable cells. A recent technological advance in flow cytometry uses antibodies conjugated to elemental metal isotopes, rather than to fluorophores, to allow signal detection by atomic mass spectrometry. Unhampered by the limitations of overlapping emission fluorescence, mass cytometry increases the number of parameters that can be measured in single cells. However, mass cytometry is unable to take advantage of current fluorescent viability dyes. An alternative methodology was therefore developed here in which the platinum-containing chemotherapy drug cisplatin was used to resolve live and dead cells by mass cytometry. In a 1-min incubation step, cisplatin preferentially labeled nonviable cells from both adherent and suspension cultures, resulting in a platinum signal quantifiable by mass cytometry. This protocol was compatible with established sample processing steps for intracellular cytometry. Furthermore, the live/dead ratios were comparable between mass- and fluorescence-based cytometry. Importantly, although cisplatin is a known DNA-damaging agent, a 1-min pulse of cisplatin did not induce observable DNA damage or apoptotic responses even within 6-h post-exposure. Cisplatin can therefore be used as a viability reagent for a wide range of mass cytometry protocols. (c) 2012 International Society for Advancement of Cytometry C1 [Fienberg, Harris G.; Simonds, Erin F.; Fantl, Wendy J.; Nolan, Garry P.; Bodenmiller, Bernd] Stanford Univ, Sch Med, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Fienberg, Harris G.; Simonds, Erin F.; Fantl, Wendy J.; Nolan, Garry P.; Bodenmiller, Bernd] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. C1 [Fienberg, Harris G.; Simonds, Erin F.; Fantl, Wendy J.; Nolan, Garry P.; Bodenmiller, Bernd] Stanford Univ, Sch Med, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Fienberg, Harris G.; Simonds, Erin F.; Fantl, Wendy J.; Nolan, Garry P.; Bodenmiller, Bernd] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. RP Nolan, GP (reprint author), 269 Campus Dr,CCSR 3205, Stanford, CA 94305 USA. EM gnolan@stanford.edu; bernd.bodenmiller@imls.uzh.ch EM gnolan@stanford.edu; bernd.bodenmiller@imls.uzh.ch RI Nolan, Garry/AAE-7903-2019 OI Simonds, Erin/0000-0002-3497-4861 FU Bill and Melinda Gates FoundationGates Foundation [GF12141-137101]; Lucille P Markey Stanford Graduate Fellowship; Swiss National Science FoundationSwiss National Science Foundation (SNSF); European Molecular Biology OrganizationEuropean Molecular Biology Organization (EMBO); Marie Curie IOFEuropean Union (EU); Rachford and Carlota A. Harris Endowed Professorship; [P01 CA034233 (NCI)]; [1R01CA130826 (NCI)]; [RFA CA 09-011 (NCI)]; [U54CA149145 (NCI)]; [5U54CA143907 (NCI)]; [U19 AI057229 (NIAID)]; [HHSN272200700038C (NIAID)]; [DR1-01477 (CIRM)]; [RB2-01592 (CIRM)]; [NHLBI-HV-10-05(2) (NHLBI)]; [HEALTH.2010.1.2-1 (European Commission)] FX Grant numbers: P01 CA034233 (NCI), 1R01CA130826 (NCI), RFA CA 09-011 (NCI), U54CA149145 (NCI), 5U54CA143907 (NCI), U19 AI057229 (NIAID), HHSN272200700038C (NIAID), DR1-01477 (CIRM), RB2-01592 (CIRM), NHLBI-HV-10-05(2) (NHLBI), HEALTH.2010.1.2-1 (European Commission), and GF12141-137101 (Bill and Melinda Gates Foundation). Grant sponsors: Lucille P Markey Stanford Graduate Fellowship (to HGF), Rachford and Carlota A. Harris Endowed Professorship (to GPN), Swiss National Science Foundation (to BB), the European Molecular Biology Organization (to BB), and the Marie Curie IOF (to BB). 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Part A PD JUN PY 2012 VL 81A IS 6 BP 467 EP 475 DI 10.1002/cyto.a.22067 PG 9 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 945FO UT WOS:000304258400008 PM 22577098 OA Green Accepted DA 2020-07-01 ER PT J AU Bjornson, ZB Nolan, GP Fantl, WJ AF Bjornson, Zach B. Nolan, Garry P. Fantl, Wendy J. TI Single-cell mass cytometry for analysis of immune system functional states SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID POLYCHROMATIC FLOW-CYTOMETRY; ELEMENT-TAGGED IMMUNOASSAY; REGULATORY T-CELLS; DIFFERENTIAL IMMUNE; VIRUS-INFECTION; SOLID TUMOR; ICP-MS; CYCLE; RESPONSES; INFLAMMATION AB Mass cytometry facilitates high-dimensional, quantitative analysis of the effects of bioactive molecules on cell populations at single-cell resolution. Datasets are generated with panels of up to 45 antibodies. Each antibody is conjugated to a polymer chelated with a stable metal isotope, usually in the lanthanide series of the periodic table. Antibody panels recognize surface markers to delineate cell types simultaneously with intracellular signaling molecules to measure biological functions, such as metabolism, survival, DNA damage, cell cycle and apoptosis, to provide an overall determination of the network state of an individual cell. This review will cover the basics of mass cytometry as well as outline assays developed for the platform that enhance the immunologist's analytical arsenal. C1 [Bjornson, Zach B.; Nolan, Garry P.; Fantl, Wendy J.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. C1 [Bjornson, Zach B.; Nolan, Garry P.; Fantl, Wendy J.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. RP Nolan, GP (reprint author), Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, 269 Campus Dr, Stanford, CA 94305 USA. EM gnolan@stanford.edu; wjfantl@stanford.edu EM gnolan@stanford.edu; wjfantl@stanford.edu RI Nolan, Garry/AAE-7903-2019 FU Rachford and Carlota A. Harris Endowed Chair; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19 AI057229, R01CA130826, U54CA149145, N01-HV-00242, 5-24927, 5U54CA143907]; FDAUnited States Department of Health & Human Services [HHSF223201210194C]; CIRMCalifornia Institute for Regenerative Medicine [DR1-01477, RB2-01592]; European Commission grantEuropean Commission Joint Research Centre [HEALTH.2010.1.2-1]; DoD CDMRP Teal Innovator Award FX The authors wish to thank Drs Scott Tanner, Olga Omatsky, Dmitry Bandura, Mitch Winnik and Mark Nitz for their critical reading of this manuscript. This work was supported by the Rachford and Carlota A. Harris Endowed Chair to GPN as well as NIH grants U19 AI057229, 1R01CA130826, U54CA149145, N01-HV-00242, 5-24927, 5U54CA143907, FDA contract HHSF223201210194C, CIRM grants DR1-01477 and RB2-01592, European Commission grant HEALTH.2010.1.2-1 and a DoD CDMRP Teal Innovator Award. Conflict of interest statement: G.P.N. has personal financial interest in the company DVS Sciences, the manufacturers of the instrument and reagents described in this manuscript. 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Opin. Immunol. PD AUG PY 2013 VL 25 IS 4 BP 484 EP 494 DI 10.1016/j.coi.2013.07.004 PG 11 WC Immunology SC Immunology GA 229BT UT WOS:000325237500010 PM 23999316 OA Green Accepted DA 2020-07-01 ER PT J AU Wu, MY Singh, AK AF Wu, Meiye Singh, Anup K. TI Single-cell protein analysis SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Review ID FLOW-CYTOMETRY; MASS CYTOMETRY; IDENTIFICATION; TRANSCRIPTOME; ENUMERATION; NETWORKS; DYNAMICS; ELISPOT; IMMUNE AB Heterogeneity of cellular systems has been widely recognized but only recently have tools become available that allow probing of genes and proteins in single cells to understand it. While the advancement in single cell genomic analysis has been greatly aided by the power of amplification techniques (e.g. PCR), analysis of proteins in single cells has proven to be more challenging. However, recent advances in multi-parameter flow cytometry, microscopy, microfluidics and other techniques have made it possible to measure wide variety of proteins in single cells. In this review, we highlight key recent developments in analysis of proteins in a single cell (excluding imaging-based methods), and discuss their significance in biological research. C1 [Wu, Meiye; Singh, Anup K.] Sandia Natl Labs, Dept Bioengn & Biotechnol, Livermore, CA 94550 USA. C1 [Wu, Meiye; Singh, Anup K.] Sandia Natl Labs, Dept Bioengn & Biotechnol, Livermore, CA 94550 USA. RP Singh, AK (reprint author), Sandia Natl Labs, Dept Bioengn & Biotechnol, Livermore, CA 94550 USA. EM aksingh@sandia.gov EM aksingh@sandia.gov OI Wu, Meiye/0000-0003-3712-1554 FU NIDCRUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [R01 DE020891, P50GM085273]; NIGMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS); ENIGMA, a Lawrence Berkeley National LaboratoryEuropean Union (EU); U.S. Department of Energy, Office of Science, Office of Biological and Environmental ResearchUnited States Department of Energy (DOE); United States Department of EnergyUnited States Department of Energy (DOE) [DE-AC04-94AL85000] FX Financial support for preparation and some of the work included was provided by the grants: R01 DE020891, funded by the NIDCR; P50GM085273 (the New Mexico Spatiotemporal Modeling Center) funded by the NIGMS; and ENIGMA, a Lawrence Berkeley National Laboratory Scientific Focus Area Program supported by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research. Sandia is a multi-program laboratory operated by Sandia Corp., a Lockheed Martin Co., for the United States Department of Energy under Contract DE-AC04-94AL85000. 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Opin. Biotechnol. PD FEB PY 2012 VL 23 IS 1 BP 83 EP 88 DI 10.1016/j.copbio.2011.11.023 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 900DZ UT WOS:000300868100014 PM 22189001 OA Green Accepted DA 2020-07-01 ER PT J AU Weber, LM Robinson, MD AF Weber, Lukas M. Robinson, Mark D. TI Comparison of Clustering Methods for High-Dimensional Single-Cell Flow and Mass Cytometry Data SO CYTOMETRY PART A LA English DT Article DE flow cytometry; mass cytometry; CyTOF; bioinformatics; clustering; manual gating; F1 score; high-dimensional; single-cell; cell populations ID AUTOMATED IDENTIFICATION; POPULATIONS; BIOCONDUCTOR; SUBSETS; REVEALS; IMMUNE AB Recent technological developments in high-dimensional flow cytometry and mass cytometry (CyTOF) have made it possible to detect expression levels of dozens of protein markers in thousands of cells per second, allowing cell populations to be characterized in unprecedented detail. Traditional data analysis by "manual gating" can be inefficient and unreliable in these high-dimensional settings, which has led to the development of a large number of automated analysis methods. Methods designed for unsupervised analysis use specialized clustering algorithms to detect and define cell populations for further downstream analysis. Here, we have performed an up-to-date, extensible performance comparison of clustering methods for high-dimensional flow and mass cytometry data. We evaluated methods using several publicly available data sets from experiments in immunology, containing both major and rare cell populations, with cell population identities from expert manual gating as the reference standard. Several methods performed well, including FlowSOM, X-shift, PhenoGraph, Rclusterpp, and flowMeans. Among these, FlowSOM had extremely fast runtimes, making this method well-suited for interactive, exploratory analysis of large, high-dimensional data sets on a standard laptop or desktop computer. These results extend previously published comparisons by focusing on high-dimensional data and including new methods developed for CyTOF data. R scripts to reproduce all analyses are available from GitHub (https://github.com/lmweber/cytometry-clustering-comparison), and pre-processed data files are available from Flow Repository (FR-FCM-ZZPH), allowing our comparisons to be extended to include new clustering methods and reference data sets. (C) 2016 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC. C1 [Weber, Lukas M.; Robinson, Mark D.] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. [Weber, Lukas M.; Robinson, Mark D.] Univ Zurich, SIB Swiss Inst Bioinformat, Zurich, Switzerland. C1 [Weber, Lukas M.; Robinson, Mark D.] Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. [Weber, Lukas M.; Robinson, Mark D.] Univ Zurich, SIB Swiss Inst Bioinformat, Zurich, Switzerland. RP Robinson, MD (reprint author), Univ Zurich, Inst Mol Life Sci, Zurich, Switzerland. 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Part A PD DEC PY 2016 VL 89A IS 12 BP 1084 EP 1096 DI 10.1002/cyto.a.23030 PG 13 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EI7ZU UT WOS:000392724500006 PM 27992111 OA Green Accepted, Other Gold DA 2020-07-01 ER PT J AU Zunder, ER Lujan, E Goltsev, Y Wernig, M Nolan, GP AF Zunder, Eli R. Lujan, Ernesto Goltsev, Yury Wernig, Marius Nolan, Garry P. TI A Continuous Molecular Roadmap to iPSC Reprogramming through Progression Analysis of Single-Cell Mass Cytometry SO CELL STEM CELL LA English DT Article ID PLURIPOTENT STEM-CELLS; SOMATIC-CELLS; SELF-RENEWAL; SURFACE MARKERS; C-MYC; EXPRESSION; MOUSE; PATHWAY; MURINE; DIFFERENTIATION AB To analyze cellular reprogramming at the single-cell level, mass cytometry was used to simultaneously measure markers of pluripotency, differentiation, cell-cycle status, and cellular signaling throughout the reprogramming process. Time-resolved progression analysis of the resulting data sets was used to construct a continuous molecular roadmap for three independent reprogramming systems. Although these systems varied substantially in Oct4, Sox2, Klf4, and c-Myc stoichiometry, they presented a common set of reprogramming landmarks. Early in the reprogramming process, Oct4(high) Klf4(high) cells transitioned to a CD73(high) CD104(high) CD54(low) partially reprogrammed state. Ki67(low) cells from this intermediate population reverted to a MEF-like phenotype, but Ki67(high) cells advanced through the M-E-T and then bifurcated into two distinct populations: an ESC-like Nanog(high) Sox2(high) CD54(high) population and a mesendoderm-like Nanog low Sox2 low Lin28 high CD24(high) PDGFR-alpha(high) population. The methods developed here for time-resolved, single-cell progression analysis may be used for the study of additional complex and dynamic systems, such as cancer progression and embryonic development. C1 [Zunder, Eli R.; Goltsev, Yury; Nolan, Garry P.] Stanford Univ Sch Med, Baxter Lab Stem Cell Biol, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Lujan, Ernesto; Wernig, Marius] Stanford Univ Sch Med, Dept Pathol, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Lujan, Ernesto] Stanford Univ Sch Med, Dept Genet, Stanford, CA 94305 USA. C1 [Zunder, Eli R.; Goltsev, Yury; Nolan, Garry P.] Stanford Univ Sch Med, Baxter Lab Stem Cell Biol, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Lujan, Ernesto; Wernig, Marius] Stanford Univ Sch Med, Dept Pathol, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Lujan, Ernesto] Stanford Univ Sch Med, Dept Genet, Stanford, CA 94305 USA. RP Nolan, GP (reprint author), Stanford Univ Sch Med, Baxter Lab Stem Cell Biol, Dept Microbiol & Immunol, Stanford, CA 94305 USA. EM gnolan@stanford.edu EM gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019 FU NIH NRSAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [F32 GM093508-01]; California Institute for Regenerative Medicine (CIRM)California Institute for Regenerative Medicine [TG2-01159]; National Science Foundation (NSF) Graduate Research FellowshipNational Science Foundation (NSF) [DGE-114747]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19 AI057229, U54CA149145, N01-HV-00242, 1U19AI100627, 5R01AI07372405, R01CA184968, 1 R33 CA183654, R33 CA183692]; NIH-Baylor Research Institute [41000411217]; NIH-Northrop Grumman [7500108142]; CIRMCalifornia Institute for Regenerative Medicine [DR1-01477, RB2-01592]; Department of DefenseUnited States Department of Defense [OC110674, 11491122]; European CommissionEuropean Commission Joint Research Centre [Health.2010.1.2-1]; Food and Drug AdministrationUnited States Department of Health & Human Services [HHSF223201210194C]; Bill and Melinda Gates FoundationGates Foundation [OPP 1017093]; Alliance for Lupus Research; Entertainment Industry Foundation (NWCRA); Rachford and Carlota A. Harris Endowed Professorship FX We thank Angelica Trejo and Astraea Jager for mass cytometry quality control and instrument maintenance. We thank the Stanford Shared FACS Facility for assistance with cell sorting. We thank the Stanford PAN Facility for assistance with microarray hybridization and imaging. We thank Rob Bruggner for patiently answering our questions about the R programming language. We thank Sean Bendall and David Burns for helpful discussions. We thank Alex Chang for assistance with immunofluorescence microscopy. E.R.Z. was supported by NIH NRSA F32 GM093508-01. E.L. was supported by the California Institute for Regenerative Medicine (CIRM) Predoctoral Fellowship TG2-01159 and the National Science Foundation (NSF) Graduate Research Fellowship DGE-114747. M.W. is a New York Stem Cell Foundation-Robertson Investigator and a Tashia and John Morgridge Faculty Scholar at the Child Health Research Institute at Stanford. This work was supported by NIH (U19 AI057229, U54CA149145, N01-HV-00242, 1U19AI100627, 5R01AI07372405, R01CA184968, 1 R33 CA183654, and R33 CA183692), NIH-Baylor Research Institute (41000411217), NIH-Northrop Grumman (7500108142), CIRM (DR1-01477 and RB2-01592), Department of Defense (OC110674 and 11491122), European Commission (Health.2010.1.2-1), Food and Drug Administration (HHSF223201210194C), Bill and Melinda Gates Foundation (OPP 1017093), the Alliance for Lupus Research, the Entertainment Industry Foundation (NWCRA grant), and the Rachford and Carlota A. Harris Endowed Professorship to G.P.N. G.P.N. has personal financial interest in the company Fluidigm, the manufacturer of the mass cytometer used in this manuscript. 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S. McGranahan, Nicholas Rosenthal, Rachel Straten, Per Thor Szallasi, Zoltan Svane, Inge Marie Swanton, Charles Quezada, Sergio A. Jakobsen, Soren Nyboe Eklund, Aron Charles Hadrup, Sine Reker TI Large-scale detection of antigen-specific T cells using peptide-MHC-I multimers labeled with DNA barcodes SO NATURE BIOTECHNOLOGY LA English DT Article ID PARALLEL DETECTION; MASS CYTOMETRY; SELF-ANTIGEN; RESPONSES; MELANOMA; GENERATION; DESIGN; SENSITIVITY; RECOGNIZES; BLOCKADE AB Identification of the peptides recognized by individual T cells is important for understanding and treating immune-related diseases. Current cytometry-based approaches are limited to the simultaneous screening of 10-100 distinct T-cell specificities in one sample. Here we use peptide-major histocompatibility complex (MHC) multimers labeled with individual DNA barcodes to screen >1,000 peptide specificities in a single sample, and detect low-frequency CD8 T cells specific for virus- or cancer restricted antigens. When analyzing T-cell recognition of shared melanoma antigens before and after adoptive cell therapy in melanoma patients, we observe a greater number of melanoma-specific T-cell populations compared with cytometry-based approaches. Furthermore, we detect neoepitope-specific T cells in tumor-infiltrating lymphocytes and peripheral blood from patients with non-small cell lung cancer. Barcode-labeled pMHC multimers enable the combination of functional T-cell analysis with large-scale epitope recognition profiling for the characterization of T-cell recognition in various diseases, including in small clinical samples. C1 [Bentzen, Amalie Kai; Lyngaa, Rikke; Saini, Sunil Kumar; Ramskov, Sofie; Such, Lina; Jakobsen, Soren Nyboe; Hadrup, Sine Reker] Tech Univ Denmark, Natl Vet Inst, Sect Immunol & Vaccinol, Copenhagen, Denmark. [Marquard, Andrea Marion; Szallasi, Zoltan; Eklund, Aron Charles] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, Lyngby, Denmark. [Donia, Marco; Straten, Per Thor; Svane, Inge Marie] Univ Copenhagen, Herlev Hosp, Dept Hematol, Ctr Canc Immune Therapy, Copenhagen, Denmark. [Donia, Marco; Svane, Inge Marie] Univ Copenhagen, Herlev Hosp, Dept Oncol, Copenhagen, Denmark. [Furness, Andrew J. S.; McGranahan, Nicholas; Rosenthal, Rachel; Swanton, Charles; Quezada, Sergio A.] UCL Canc Inst, CRUK Lung Canc Ctr Excellence, London, England. [Furness, Andrew J. S.; Quezada, Sergio A.] UCL, UCL Canc Inst, Canc Immunol Unit, London, England. [McGranahan, Nicholas; Rosenthal, Rachel; Swanton, Charles] Francis Crick Inst, Translat Canc Therapeut Lab, London, England. [Straten, Per Thor] Univ Copenhagen, Dept Immunol & Microbiol, Copenhagen, Denmark. [Jakobsen, Soren Nyboe] Immudex, Copenhagen, Denmark. C1 [Bentzen, Amalie Kai; Lyngaa, Rikke; Saini, Sunil Kumar; Ramskov, Sofie; Such, Lina; Jakobsen, Soren Nyboe; Hadrup, Sine Reker] Tech Univ Denmark, Natl Vet Inst, Sect Immunol & Vaccinol, Copenhagen, Denmark. [Marquard, Andrea Marion; Szallasi, Zoltan; Eklund, Aron Charles] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, Lyngby, Denmark. [Donia, Marco; Straten, Per Thor; Svane, Inge Marie] Univ Copenhagen, Herlev Hosp, Dept Hematol, Ctr Canc Immune Therapy, Copenhagen, Denmark. [Donia, Marco; Svane, Inge Marie] Univ Copenhagen, Herlev Hosp, Dept Oncol, Copenhagen, Denmark. [Furness, Andrew J. S.; McGranahan, Nicholas; Rosenthal, Rachel; Swanton, Charles; Quezada, Sergio A.] UCL Canc Inst, CRUK Lung Canc Ctr Excellence, London, England. [Furness, Andrew J. S.; Quezada, Sergio A.] UCL, UCL Canc Inst, Canc Immunol Unit, London, England. [McGranahan, Nicholas; Rosenthal, Rachel; Swanton, Charles] Francis Crick Inst, Translat Canc Therapeut Lab, London, England. [Straten, Per Thor] Univ Copenhagen, Dept Immunol & Microbiol, Copenhagen, Denmark. [Jakobsen, Soren Nyboe] Immudex, Copenhagen, Denmark. RP Hadrup, SR (reprint author), Tech Univ Denmark, Natl Vet Inst, Sect Immunol & Vaccinol, Copenhagen, Denmark. EM sirha@vet.dtu.dk EM sirha@vet.dtu.dk RI Hadrup, Sine Reker/P-3388-2014 OI Hadrup, Sine Reker/0000-0002-5937-4344; Quezada, Sergio/0000-0002-9763-1700; Marquard, Andrea/0000-0003-2928-6017; Saini, Sunil Kumar/0000-0003-3382-9432; Svane, Inge Marie/0000-0002-9451-6037; Szallasi, Zoltan/0000-0001-5395-7509; Ramskov, Sofie/0000-0001-9413-8673; Donia, Marco/0000-0003-4966-9752; jakobsen, soren nyboe/0000-0002-2227-8615; thor Straten, Per/0000-0002-4731-4969; Swanton, Charles/0000-0002-4299-3018; McGranahan, Nicholas/0000-0001-9537-4045; Eklund, Aron Charles/0000-0003-0861-1001 FU Danish Cancer SocietyDanish Cancer Society [ID:R72-A4531-13-S2]; Lundbeck Foundation Fellowship [R190-2014-4178]; Danish Research Council (FSS)Det Frie Forskningsrad (DFF)Danish Medical Research Council [1331-00283]; Danish Research Council (DFF) [4004-00422]; Familien Erichsens Mindefond; Cancer Research UKCancer Research UK [FC001169]; UK Medical Research CouncilMedical Research Council UK (MRC) [FC001169, MR/FC001169/1]; Wellcome TrustWellcome Trust [FC001169]; Novo Nordisk FoundationNovo Nordisk Foundation [16584]; Cancer Research UKCancer Research UK [12100, 20265, 20466]; Lundbeck FoundationLundbeckfonden [R181-2014-3828]; Novo Nordisk FondenNovo NordiskNovo Nordisk Foundation [NNF15OC0016584] FX We would like to thank U.K. Hansen, A. 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Biotechnol. PD OCT PY 2016 VL 34 IS 10 BP 1037 EP 1045 DI 10.1038/nbt.3662 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EA0ZG UT WOS:000386317500018 PM 27571370 DA 2020-07-01 ER PT J AU Wong, MT Ong, DEH Lim, FSH Teng, KWW McGovern, N Narayanan, S Ho, WQ Cerny, D Tan, HKK Anicete, R Tan, BK Lim, TKH Chan, CY Cheow, PC Lee, SY Takano, A Tan, EH Tam, JKC Tan, EY Chan, JKY Fink, K Bertoletti, A Ginhoux, F De Lafaille, MAC Newell, EW AF Wong, Michael Thomas Ong, David Eng Hui Lim, Frances Sheau Huei Teng, Karen Wei Weng McGovern, Naomi Narayanan, Sriram Ho, Wen Qi Cerny, Daniela Tan, Henry Kun Kiaang Anicete, Rosslyn Tan, Bien Keem Lim, Tony Kiat Hon Chan, Chung Yip Cheow, Peng Chung Lee, Ser Yee Takano, Angela Tan, Eng-Huat Tam, John Kit Chung Tan, Ern Yu Chan, Jerry Kok Yen Fink, Katja Bertoletti, Antonio Ginhoux, Florent De Lafaille, Maria Alicia Curotto Newell, Evan William TI A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures SO IMMUNITY LA English DT Article ID CHEMOKINE RECEPTOR EXPRESSION; MASS CYTOMETRY; INTERLEUKIN 22; TGF-BETA; DIFFERENTIATION; IMMUNITY; DISTINCT; SUBSET; COMPARTMENTALIZATION; LYMPHOCYTES AB Depending on the tissue microenvironment, T cells can differentiate into highly diverse subsets expressing unique trafficking receptors and cytokines. Studies of human lymphocytes have primarily focused on a limited number of parameters in blood, representing an incomplete view of the human immune system. Here, we have utilized mass cytometry to simultaneously analyze T cell trafficking and functional markers across eight different human tissues, including blood, lymphoid, and non-lymphoid tissues. These data have revealed that combinatorial expression of trafficking receptors and cytokines better defines tissue specificity. Notably, we identified numerous T helper cell subsets with overlapping cytokine expression, but only specific cytokine combinations are secreted regardless of tissue type. This indicates that T cell lineages defined in mouse models cannot be clearly distinguished in humans. Overall, our data uncover a plethora of tissue immune signatures and provide a systemic map of how T cell phenotypes are altered throughout the human body. C1 [Wong, Michael Thomas; Teng, Karen Wei Weng; McGovern, Naomi; Narayanan, Sriram; Ho, Wen Qi; Cerny, Daniela; Fink, Katja; Bertoletti, Antonio; Ginhoux, Florent; De Lafaille, Maria Alicia Curotto; Newell, Evan William] Singapore Immunol Network SIgN, A STAR, Singapore 138648, Singapore. [Ong, David Eng Hui] Natl Univ Hlth Syst, Univ Med Cluster, Div Gastroenterol & Hepatol, Singapore 119228, Singapore. [Lim, Frances Sheau Huei] Natl Univ Hlth Syst, Univ Surg Ctr, Div Colorectal Surg, Singapore 119228, Singapore. [Cerny, Daniela] Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore. [Tan, Henry Kun Kiaang; Anicete, Rosslyn] KK Womens & Childrens Hosp, Dept Otolaryngol, Singapore 229899, Singapore. [Tan, Bien Keem] Singapore Gen Hosp, Dept Plast Reconstruct & Aesthet Surg, Singapore 169608, Singapore. [Lim, Tony Kiat Hon; Takano, Angela] Singapore Gen Hosp, Dept Pathol, Singapore 169856, Singapore. [Chan, Chung Yip; Cheow, Peng Chung; Lee, Ser Yee] Singapore Gen Hosp, Dept Hepatopancreatobiliary & Transplant Surg, Singapore 169856, Singapore. [Tan, Eng-Huat] Natl Canc Ctr, Dept Med Oncol, Singapore 169610, Singapore. [Tam, John Kit Chung] Natl Univ Singapore, Dept Surg, Singapore 119228, Singapore. [Tan, Ern Yu] Tan Tock Seng Hosp, Dept Gen Surg, Singapore 308433, Singapore. [Chan, Jerry Kok Yen] KK Womens & Childrens Hosp, Dept Reprod Med, Singapore 229899, Singapore. [Bertoletti, Antonio] Duke NUS Med Sch, Emerging Infect Dis EID Program, Singapore 169857, Singapore. C1 [Wong, Michael Thomas; Teng, Karen Wei Weng; McGovern, Naomi; Narayanan, Sriram; Ho, Wen Qi; Cerny, Daniela; Fink, Katja; Bertoletti, Antonio; Ginhoux, Florent; De Lafaille, Maria Alicia Curotto; Newell, Evan William] Singapore Immunol Network SIgN, A STAR, Singapore 138648, Singapore. [Ong, David Eng Hui] Natl Univ Hlth Syst, Univ Med Cluster, Div Gastroenterol & Hepatol, Singapore 119228, Singapore. [Lim, Frances Sheau Huei] Natl Univ Hlth Syst, Univ Surg Ctr, Div Colorectal Surg, Singapore 119228, Singapore. [Cerny, Daniela] Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore. [Tan, Henry Kun Kiaang; Anicete, Rosslyn] KK Womens & Childrens Hosp, Dept Otolaryngol, Singapore 229899, Singapore. [Tan, Bien Keem] Singapore Gen Hosp, Dept Plast Reconstruct & Aesthet Surg, Singapore 169608, Singapore. [Lim, Tony Kiat Hon; Takano, Angela] Singapore Gen Hosp, Dept Pathol, Singapore 169856, Singapore. [Chan, Chung Yip; Cheow, Peng Chung; Lee, Ser Yee] Singapore Gen Hosp, Dept Hepatopancreatobiliary & Transplant Surg, Singapore 169856, Singapore. [Tan, Eng-Huat] Natl Canc Ctr, Dept Med Oncol, Singapore 169610, Singapore. [Tam, John Kit Chung] Natl Univ Singapore, Dept Surg, Singapore 119228, Singapore. [Tan, Ern Yu] Tan Tock Seng Hosp, Dept Gen Surg, Singapore 308433, Singapore. [Chan, Jerry Kok Yen] KK Womens & Childrens Hosp, Dept Reprod Med, Singapore 229899, Singapore. [Bertoletti, Antonio] Duke NUS Med Sch, Emerging Infect Dis EID Program, Singapore 169857, Singapore. RP Wong, MT; Newell, EW (reprint author), Singapore Immunol Network SIgN, A STAR, Singapore 138648, Singapore. EM michael.thomas.wong@merck.com; evan_newell@immunol.a-star.edu.sg EM michael.thomas.wong@merck.com; evan_newell@immunol.a-star.edu.sg RI Newell, Evan/AAE-9470-2020; Newell, Evan W/F-9711-2012; Lim, Frances/B-5168-2011; Tam, John/B-6048-2012 OI Newell, Evan/0000-0002-2889-243X; Newell, Evan W/0000-0002-2889-243X; McGovern, Naomi/0000-0001-5200-2698 FU A-STAR/SIgN core funding; A-STAR/SIgN immunomonitoring platform funding; Singapore Translational Research (STaR) Investigator Award [NMRC/STaR/013/2012] FX The authors thank the Singapore Immunology Network (SIgN) community and all members of the Newell lab for helpful discussion and technical support. We thank the Clinical Trials Resource Centre (Singapore General Hospital) for providing select skin samples and the National Cancer Center Singapore (NCCS) Translational & Clinical Research (TCR) research coordinators for helping to provide select lung samples. We also thank Paul Klenerman and Laura Mackay for helpful comments. This study was primarily funded by A-STAR/SIgN core funding (E.W.N., F.G., M.A.C.D., and K.F.) and the A-STAR/SIgN immunomonitoring platform funding (E.W.N.) and was partially supported by a Singapore Translational Research (STaR) Investigator Award (NMRC/STaR/013/2012) to A. B. 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Mingueneau, Michael Bendall, Sean C. Litvin, Oren Stone, Erica Pe'er, Dana Nolan, Garry P. TI Conditional density-based analysis of T cell signaling in single-cell data SO SCIENCE LA English DT Article ID MASS CYTOMETRY; MUTUAL INFORMATION; CD4; ACTIVATION; GENERATION; RESPONSES; PATHWAYS; IMMUNE; NAIVE AB Cellular circuits sense the environment, process signals, and compute decisions using networks of interacting proteins. To model such a system, the abundance of each activated protein species can be described as a stochastic function of the abundance of other proteins. High-dimensional single-cell technologies, such as mass cytometry, offer an opportunity to characterize signaling circuit-wide. However, the challenge of developing and applying computational approaches to interpret such complex data remains. Here, we developed computational methods, based on established statistical concepts, to characterize signaling network relationships by quantifying the strengths of network edges and deriving signaling response functions. In comparing signaling between naive and antigen-exposed CD4(+) T lymphocytes, we find that although these two cell subtypes had similarly wired networks, naive cells transmitted more information along a key signaling cascade than did antigen-exposed cells. We validated our characterization on mice lacking the extracellular-regulated mitogen-activated protein kinase (MAPK) ERK2, which showed stronger influence of pERK on pS6 (phosphorylated-ribosomal protein S6), in naive cells as compared with antigen-exposed cells, as predicted. We demonstrate that by using cell-to-cell variation inherent in single-cell data, we can derive response functions underlying molecular circuits and drive the understanding of how cells process signals. C1 [Krishnaswamy, Smita; Litvin, Oren; Pe'er, Dana] Columbia Univ, Dept Biol Sci, Dept Syst Biol, New York, NY 10027 USA. [Spitzer, Matthew H.; Bendall, Sean C.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Mingueneau, Michael] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA USA. [Stone, Erica] Univ Calif San Diego, Dept Cellular & Mol Med, Div Biol Sci, Mol Biol Sect, La Jolla, CA 92093 USA. C1 [Krishnaswamy, Smita; Litvin, Oren; Pe'er, Dana] Columbia Univ, Dept Biol Sci, Dept Syst Biol, New York, NY 10027 USA. [Spitzer, Matthew H.; Bendall, Sean C.; Nolan, Garry P.] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Stanford, CA 94305 USA. [Mingueneau, Michael] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA USA. [Stone, Erica] Univ Calif San Diego, Dept Cellular & Mol Med, Div Biol Sci, Mol Biol Sect, La Jolla, CA 92093 USA. RP Pe'er, D (reprint author), Columbia Univ, Dept Biol Sci, Dept Syst Biol, New York, NY 10027 USA. EM dpeer@biology.columbia.edu EM dpeer@biology.columbia.edu RI Krishnaswamy, Smita/D-8089-2016; Nolan, Garry/AAE-7903-2019; Mingueneau, Michael/O-5313-2019 OI Krishnaswamy, Smita/0000-0001-5823-1985; Mingueneau, Michael/0000-0002-3873-7329; Spitzer, Matthew/0000-0002-5291-3819 FU National Science Foundation CAREER awardNational Science Foundation (NSF) [MCB-1149728]; National Centers for Biomedical Computing Grant [1U54CA121852-01A1]; NIH S10 Shared instrumentation grant [NIH S10 SIG S10RR027582-01]; Packard Fellowship for Science and Engineering; Damon Runyon Cancer Research Foundation Fellowship [DRG-2017-09]; NIH K01 award [1K01DK095008]; Rachford and Carlota A. Harris Endowed Professorship; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [RFA CA 09-011, NHLBIHV-10-05 (2)]; European CommissionEuropean Commission Joint Research Centre [HEALTH.2010.1.2-1]; Bill and Melinda Gates FoundationGates Foundation [GF12141-137101]; [U19 AI057229]; [P01 CA034233]; [HHSN272200700038C]; [1R01CA130826]; [CIRM DR1-01477]; [RB2-01592] FX We thank B. Bodenmiller, N. Friedman, N. HaCohen, I. Pe'er, A. Regev, and S. Reiner for valuable comments. We respectfully appreciate the provision of mouse samples and key mechanistic discussions with C. Benoist and S. Hedrick. This research was supported by the National Science Foundation CAREER award through grant MCB-1149728 and National Centers for Biomedical Computing Grant 1U54CA121852-01A1 and the NIH S10 Shared instrumentation grant NIH S10 SIG S10RR027582-01. D. P. holds a Packard Fellowship for Science and Engineering. S. C. B. is supported by the Damon Runyon Cancer Research Foundation Fellowship (DRG-2017-09). E. S. is supported by NIH K01 award 1K01DK095008. G. P. N. is supported by the Rachford and Carlota A. Harris Endowed Professorship and grants from U19 AI057229, P01 CA034233, HHSN272200700038C, 1R01CA130826, CIRM DR1-01477, and RB2-01592, NCI RFA CA 09-011, NHLBIHV-10-05 (2), European Commission HEALTH.2010.1.2-1, and the Bill and Melinda Gates Foundation (GF12141-137101). S. K., G. P. N., and D. P. conceived the study. S. K. and D. P. designed and developed DREVI, DREMI, and additional computational methods in this manuscript. S. K. wrote all computer programs used in this manuscript. M. H. S. and S. C. B. developed reagents. M. M. stimulated the mice and collected the biological samples. M. H. S., M. M., and S. C. B. designed mouse experiments and performed cognate data acquisition. E. S. developed the inducible ERK-knockdown mouse. S. K. and O.L. performed statistical analysis. S. K. and D. P. performed the biological analysis and interpretation. S. K., G. P. N., and D. P. wrote the manuscript. 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Mrdjen, Dunja Tosevski, Vinko Krieg, Carsten Becher, Burkhard TI The end of gating? An introduction to automated analysis of high dimensional cytometry data SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Review DE Citrus; CyTOF; Data analysis; Flow cytometry; Mass cytometry; PSM; PhenoGraph; SPADE; t-SNE; Wanderlust ID HUMAN B-CELL; FLOW-CYTOMETRY; MASS CYTOMETRY; BIOLOGICAL CELLS; IDENTIFICATION; NORMALIZATION; POPULATIONS; PHENOTYPE; IMMUNE; GUIDE AB Ever since its invention half a century ago, flow cytometry has been a major tool for single-cell analysis, fueling advances in our understanding of a variety of complex cellular systems, in particular the immune system. The last decade has witnessed significant technical improvements in available cytometry platforms, such that more than 20 parameters can be analyzed on a single-cell level by fluorescence-based flow cytometry. The advent of mass cytometry has pushed this limit up to, currently, 50 parameters. However, traditional analysis approaches for the resulting high-dimensional datasets, such as gating on bivariate dot plots, have proven to be inefficient. Although a variety of novel computational analysis approaches to interpret these datasets are already available, they have not yet made it into the mainstream and remain largely unknown to many immunologists. Therefore, this review aims at providing a practical overview of novel analysis techniques for high-dimensional cytometry data including SPADE, t-SNE, Wanderlust, Citrus, and PhenoGraph, and how these applications can be used advantageously not only for the most complex datasets, but also for standard 14-parameter cytometry datasets. C1 [Mair, Florian; Hartmann, Felix J.; Mrdjen, Dunja; Tosevski, Vinko; Krieg, Carsten; Becher, Burkhard] Univ Zurich, Inst Expt Immunol, CH-8091 Zurich, Switzerland. C1 [Mair, Florian; Hartmann, Felix J.; Mrdjen, Dunja; Tosevski, Vinko; Krieg, Carsten; Becher, Burkhard] Univ Zurich, Inst Expt Immunol, CH-8091 Zurich, Switzerland. RP Becher, B (reprint author), Univ Zurich, Inst Expt Immunol, Sternwartstr 2, CH-8091 Zurich, Switzerland. EM becher@immunology.uzh.ch EM becher@immunology.uzh.ch OI Krieg, Carsten/0000-0002-5145-7591; Becher, Burkhard/0000-0002-1541-7867; Mrdjen, Dunja/0000-0001-9269-2806; Mair, Florian/0000-0001-6732-5449; Hartmann, Felix/0000-0002-4174-2276 FU Swiss National Science Foundation (SNF)Swiss National Science Foundation (SNSF) [316030_150768, 310030_146130, CRSII3_136203]; European Union FP7 project TargetBraIn; ATECT; University Research Priority Project: Translational cancer research; NeuroKine FX This work was supported by grants from the Swiss National Science Foundation (SNF, accession numbers 316030_150768, 310030_146130, and CRSII3_136203), the European Union FP7 project TargetBraIn, NeuroKine, and ATECT and the University Research Priority Project: Translational cancer research. 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J. Immunol. PD JAN PY 2016 VL 46 IS 1 BP 34 EP 43 DI 10.1002/eji.201545774 PG 10 WC Immunology SC Immunology GA DB0YO UT WOS:000368234800005 PM 26548301 DA 2020-07-01 ER PT J AU Kidd, BA Peters, LA Schadt, EE Dudley, JT AF Kidd, Brian A. Peters, Lauren A. Schadt, Eric E. Dudley, Joel T. TI Unifying immunology with informatics and multiscale biology SO NATURE IMMUNOLOGY LA English DT Review ID DIFFERENTIAL EXPRESSION ANALYSIS; CHIP-SEQ EXPERIMENTS; HLA CLASS-I; GENE-EXPRESSION; SYSTEMS-BIOLOGY; HIGH-THROUGHPUT; REGULATORY NETWORKS; ENRICHMENT ANALYSIS; MASS CYTOMETRY; RNA-SEQ AB The immune system is a highly complex and dynamic system. Historically, the most common scientific and clinical practice has been to evaluate its individual components. This kind of approach cannot always expose the interconnecting pathways that control immune-system responses and does not reveal how the immune system works across multiple biological systems and scales. High-throughput technologies can be used to measure thousands of parameters of the immune system at a genome-wide scale. These system-wide surveys yield massive amounts of quantitative data that provide a means to monitor and probe immune-system function. New integrative analyses can help synthesize and transform these data into valuable biological insight. Here we review some of the computational analysis tools for high-dimensional data and how they can be applied to immunology. C1 [Kidd, Brian A.; Schadt, Eric E.; Dudley, Joel T.] Dept Genet & Genom Sci, New York, NY 10029 USA. [Kidd, Brian A.; Schadt, Eric E.; Dudley, Joel T.] Icahn Inst Genom & Multiscale Biol, New York, NY USA. [Kidd, Brian A.; Peters, Lauren A.; Schadt, Eric E.; Dudley, Joel T.] Icahn Sch Med Mt Sinai, New York, NY USA. [Peters, Lauren A.] Grad Sch Biomed Sci, New York, NY USA. C1 [Kidd, Brian A.; Schadt, Eric E.; Dudley, Joel T.] Dept Genet & Genom Sci, New York, NY 10029 USA. [Kidd, Brian A.; Schadt, Eric E.; Dudley, Joel T.] Icahn Inst Genom & Multiscale Biol, New York, NY USA. [Kidd, Brian A.; Peters, Lauren A.; Schadt, Eric E.; Dudley, Joel T.] Icahn Sch Med Mt Sinai, New York, NY USA. [Peters, Lauren A.] Grad Sch Biomed Sci, New York, NY USA. RP Dudley, JT (reprint author), Dept Genet & Genom Sci, New York, NY 10029 USA. EM joel.dudley@mssm.edu EM joel.dudley@mssm.edu OI Kidd, Brian/0000-0003-2110-1145 FU National Institute of Diabetes and Digestive and Kidney DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [R01 DK098242]; Pharmaceutical Research and Manufacturers of America Foundation FX We thank C. Berin, B. Brown, R. Kosoy, B. Readhead and C. Tato for critical reading and feedback on the manuscript. This work was supported by funding from the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK098242) and the Pharmaceutical Research and Manufacturers of America Foundation. 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Immunol. PD FEB PY 2014 VL 15 IS 2 BP 118 EP 127 DI 10.1038/ni.2787 PG 10 WC Immunology SC Immunology GA 295XV UT WOS:000330150600003 PM 24448569 OA Green Accepted DA 2020-07-01 ER PT J AU Krijger, PHL Di Stefano, B de Wit, E Limone, F van Oevelen, C de Laat, W Graf, T AF Krijger, Peter Hugo Lodewijk Di Stefano, Bruno de Wit, Elzo Limone, Francesco van Oevelen, Chris de Laat, Wouter Graf, Thomas TI Cell-of-Origin-Specific 3D Genome Structure Acquired during Somatic Cell Reprogramming SO CELL STEM CELL LA English DT Article ID PLURIPOTENT STEM-CELLS; CHROMATIN ARCHITECTURE; EPIGENETIC MEMORY; MASS CYTOMETRY; IPS CELLS; DIFFERENTIATION; REORGANIZATION; ORGANIZATION; PRINCIPLES; ENHANCERS AB Forced expression of reprogramming factors can convert somatic cells into induced pluripotent stem cells (iPSCs). Here we studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale topologically associated domain (TAD) repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic-cell-specific genome structures while establishing an embryonic stem-cell-like 3D genome. Yet, early passage iPSCs carry topological hallmarks that enable recognition of their cell of origin. These hallmarks are not remnants of somatic chromosome topologies. Instead, the distinguishing topological features are acquired during reprogramming, as we also find for cell-of-origin-dependent gene expression patterns. C1 [Krijger, Peter Hugo Lodewijk; de Wit, Elzo; de Laat, Wouter] Hubrecht Inst KNAW, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. [Krijger, Peter Hugo Lodewijk; de Wit, Elzo; de Laat, Wouter] Univ Med Ctr Utrecht, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. [Di Stefano, Bruno; Limone, Francesco; van Oevelen, Chris; Graf, Thomas] Ctr Genom Regulat CRG, Gene Regulat Stem Cells & Canc Programme, Dr Aiguader 88, Barcelona 08003, Spain. [Di Stefano, Bruno; Limone, Francesco; van Oevelen, Chris; Graf, Thomas] Pompeu Fabra Univ, Dr Aiguader 88, Barcelona 08003, Spain. [Di Stefano, Bruno] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Di Stefano, Bruno] Harvard Univ, Sch Med, Boston, MA 02114 USA. [de Wit, Elzo] Netherlands Canc Inst, Div Gene Regulat, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. C1 [Krijger, Peter Hugo Lodewijk; de Wit, Elzo; de Laat, Wouter] Hubrecht Inst KNAW, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. [Krijger, Peter Hugo Lodewijk; de Wit, Elzo; de Laat, Wouter] Univ Med Ctr Utrecht, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. [Di Stefano, Bruno; Limone, Francesco; van Oevelen, Chris; Graf, Thomas] Ctr Genom Regulat CRG, Gene Regulat Stem Cells & Canc Programme, Dr Aiguader 88, Barcelona 08003, Spain. [Di Stefano, Bruno; Limone, Francesco; van Oevelen, Chris; Graf, Thomas] Pompeu Fabra Univ, Dr Aiguader 88, Barcelona 08003, Spain. [Di Stefano, Bruno] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Di Stefano, Bruno] Harvard Univ, Sch Med, Boston, MA 02114 USA. [de Wit, Elzo] Netherlands Canc Inst, Div Gene Regulat, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. RP de Laat, W (reprint author), Hubrecht Inst KNAW, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands.; de Laat, W (reprint author), Univ Med Ctr Utrecht, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands.; Graf, T (reprint author), Ctr Genom Regulat CRG, Gene Regulat Stem Cells & Canc Programme, Dr Aiguader 88, Barcelona 08003, Spain.; Graf, T (reprint author), Pompeu Fabra Univ, Dr Aiguader 88, Barcelona 08003, Spain. EM w.delaat@hubrecht.eu; thomas.graf@crg.eu EM w.delaat@hubrecht.eu; thomas.graf@crg.eu RI Di Stefano, Bruno/K-5020-2017 OI Di Stefano, Bruno/0000-0003-2532-3087; Krijger, Peter/0000-0003-1702-348X; de Wit, Elzo/0000-0003-2883-1415; de Laat, Wouter/0000-0002-6393-595X FU NWO/CW TOP grantNetherlands Organization for Scientific Research (NWO) [714.012.002]; NWO VICI grantNetherlands Organization for Scientific Research (NWO) [724.012.003]; NanoNextNL grant; European Research CouncilEuropean Research Council (ERC) [209700]; Ministerio de Educacion y CienciaSpanish Government [SAF.2012-37167]; Fundacio La Marato [TV3 120410]; AGAUR SGRAgencia de Gestio D'Ajuts Universitaris de Recerca Agaur (AGAUR) [1136]; European Research Council Synergy GrantEuropean Research Council (ERC); ERC Stg [637587] FX This work was supported by an NWO/CW TOP grant (714.012.002), an NWO VICI grant 724.012.003, a NanoNextNL grant, and a European Research Council Starting Grant (209700, "4C") to W.d.L.; a Ministerio de Educacion y Ciencia, SAF.2012-37167, Fundacio La Marato TV3 120410, AGAUR SGR 1136, and European Research Council Synergy Grant ("4D-Genome) to T.G.; and an ERC Stg (637587, "HAP-PHEN") to E.d.W. CR Apostolou E, 2013, CELL STEM CELL, V12, P699, DOI 10.1016/j.stem.2013.04.013 Bar-Nur O, 2011, CELL STEM CELL, V9, P17, DOI 10.1016/j.stem.2011.06.007 Boiani M, 2002, GENE DEV, V16, P1209, DOI 10.1101/gad.966002 Buganim Y, 2013, NAT REV GENET, V14, P427, DOI 10.1038/nrg3473 Buganim Y, 2012, CELL, V150, P1209, DOI 10.1016/j.cell.2012.08.023 Carey BW, 2010, NAT METHODS, V7, P56, DOI [10.1038/NMETH.1410, 10.1038/nmeth.1410] Chandra T, 2015, CELL REP, V10, P471, DOI 10.1016/j.celrep.2014.12.055 Creyghton MP, 2010, P NATL ACAD SCI USA, V107, P21931, DOI 10.1073/pnas.1016071107 de Laat W, 2013, NATURE, V502, P499, DOI 10.1038/nature12753 de Wit E, 2013, NATURE, V501, P227, DOI 10.1038/nature12420 Denholtz M, 2013, CELL STEM CELL, V13, P602, DOI 10.1016/j.stem.2013.08.013 Di Stefano B, 2014, NATURE, V506, P235, DOI 10.1038/nature12885 Dixon JR, 2015, NATURE, V518, P331, DOI 10.1038/nature14222 Dixon JR, 2012, NATURE, V485, P376, DOI 10.1038/nature11082 Kagey MH, 2010, NATURE, V467, P430, DOI 10.1038/nature09380 Kim K, 2010, NATURE, V467, P285, DOI 10.1038/nature09342 Lane AA, 2014, NAT GENET, V46, P618, DOI 10.1038/ng.2949 Lieberman-Aiden E, 2009, SCIENCE, V326, P289, DOI 10.1126/science.1181369 Lodato MA, 2013, PLOS GENET, V9, DOI 10.1371/journal.pgen.1003288 Lujan E, 2015, NATURE, V521, P352, DOI 10.1038/nature14274 Nishino K, 2011, PLOS GENET, V7, DOI 10.1371/journal.pgen.1002085 Nora EP, 2012, NATURE, V485, P381, DOI 10.1038/nature11049 O'Malley J, 2013, NATURE, V499, P88, DOI 10.1038/nature12243 Peric-Hupkes D, 2010, MOL CELL, V38, P603, DOI 10.1016/j.molcel.2010.03.016 Phillips-Cremins JE, 2013, CELL, V153, P1281, DOI 10.1016/j.cell.2013.04.053 Polo JM, 2010, NAT BIOTECHNOL, V28, P848, DOI 10.1038/nbt.1667 Rao SSP, 2014, CELL, V159, P1665, DOI 10.1016/j.cell.2014.11.021 Sexton T, 2012, CELL, V148, P458, DOI 10.1016/j.cell.2012.01.010 Splinter E, 2012, METHODS, V58, P221, DOI 10.1016/j.ymeth.2012.04.009 Takahashi K, 2006, CELL, V126, P663, DOI 10.1016/j.cell.2006.07.024 van Oevelen C, 2008, MOL CELL, V32, P359, DOI 10.1016/j.molcel.2008.10.015 Wei Z, 2013, CELL STEM CELL, V13, P36, DOI 10.1016/j.stem.2013.05.010 Weissbein U, 2014, J CELL BIOL, V204, P153, DOI 10.1083/jcb.201310135 Whyte WA, 2013, CELL, V153, P307, DOI 10.1016/j.cell.2013.03.035 Yue F, 2014, NATURE, V515, P355, DOI 10.1038/nature13992 Zhang B, 2005, NUCLEIC ACIDS RES, V33, pW741, DOI 10.1093/nar/gki475 Zhao XY, 2009, NATURE, V461, P86, DOI 10.1038/nature08267 Zunder ER, 2015, CELL STEM CELL, V16, P323, DOI 10.1016/j.stem.2015.01.015 NR 38 TC 87 Z9 90 U1 0 U2 32 PU CELL PRESS PI CAMBRIDGE PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD MAY 5 PY 2016 VL 18 IS 5 BP 597 EP 610 DI 10.1016/j.stem.2016.01.007 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA DL4HE UT WOS:000375594200011 PM 26971819 OA Other Gold, Green Published DA 2020-07-01 ER PT J AU Samusik, N Good, Z Spitzer, MH Davis, KL Nolan, GP AF Samusik, Nikolay Good, Zinaida Spitzer, Matthew H. Davis, Kara L. Nolan, Garry P. TI Automated mapping of phenotype space with single-cell data SO NATURE METHODS LA English DT Article ID FLOW-CYTOMETRY DATA; MASS CYTOMETRY; IDENTIFICATION; POPULATIONS; RESPONSES AB Accurate identification of cell subsets in complex populations is key to discovering novelty in multidimensional single-cell experiments. We present X-shift (http://web.stanford.edu/similar to samusik/vortex/), an algorithm that processes data sets using fast k-nearest-neighbor estimation of cell event density and arranges populations by marker-based classification. X-shift enables automated cell-subset clustering and access to biological insights that 'prior knowledge' might prevent the researcher from discovering. C1 [Samusik, Nikolay; Good, Zinaida; Spitzer, Matthew H.; Davis, Kara L.; Nolan, Garry P.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Good, Zinaida; Spitzer, Matthew H.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Davis, Kara L.] Stanford Univ, Sch Med, Dept Pediat Hematol & Oncol, Stanford, CA 94305 USA. C1 [Samusik, Nikolay; Good, Zinaida; Spitzer, Matthew H.; Davis, Kara L.; Nolan, Garry P.] Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. [Good, Zinaida; Spitzer, Matthew H.] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Davis, Kara L.] Stanford Univ, Sch Med, Dept Pediat Hematol & Oncol, Stanford, CA 94305 USA. RP Nolan, GP (reprint author), Stanford Univ, Sch Med, Dept Microbiol & Immunol, Stanford, CA 94305 USA. EM gnolan@stanford.edu EM gnolan@stanford.edu RI Nolan, Garry/AAE-7903-2019 OI Spitzer, Matthew/0000-0002-5291-3819; Good, Zinaida/0000-0003-2343-5771 FU NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01GM109836, U19 AI057229, 1U19AI100627, R01-CA184968, 1R33-CA183654-01, R33-CA183692, 1R01-GM10983601, 1R21-CA183660, 1R01-NS08953301, OPP-1113682, 5UH2-AR067676, 1R01-CA19665701, R01-HL120724]; Immunology Training grant [5T32AI007290]; US Department of DefenseUnited States Department of Defense; Northrop-Grumman Corporation; US Food and Drug Administration [BAA HHSF223201210194c]; Rachford and Carlota A. Harris Endowed Chair FX We thank M. Angst, W.J. Fantl, A. Surnov, E. Freeman, and W.H. Wong for help in manuscript editing and preparation. This work was supported by NIH grant R01GM109836 (N.S.); NIH grants U19 AI057229, 1U19AI100627, R01-CA184968, 1R33-CA183654-01, R33-CA183692, 1R01-GM10983601, 1R21-CA183660, 1R01-NS08953301, OPP-1113682, 5UH2-AR067676, 1R01-CA19665701 and R01-HL120724 (G.P.N.); Immunology Training grant 5T32AI007290 (Z.G.); US Department of Defense Teal Innovator Award (G.P.N.); Northrop-Grumman Corporation (G.P.N.); the US Food and Drug Administration grant BAA HHSF223201210194c (G.P.N.) and the Rachford and Carlota A. Harris Endowed Chair (G.P.N.). 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Methods PD JUN PY 2016 VL 13 IS 6 BP 493 EP + DI 10.1038/NMETH.3863 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DO0PF UT WOS:000377480100015 PM 27183440 OA Green Accepted DA 2020-07-01 ER PT J AU Prill, RJ Saez-Rodriguez, J Alexopoulos, LG Sorger, PK Stolovitzky, G AF Prill, Robert J. Saez-Rodriguez, Julio Alexopoulos, Leonidas G. Sorger, Peter K. Stolovitzky, Gustavo TI Crowdsourcing Network Inference: The DREAM Predictive Signaling Network Challenge SO SCIENCE SIGNALING LA English DT Article ID MASS CYTOMETRY; GENE NETWORKS; CELL; RECEPTOR AB Computational analyses of systematic measurements on the states and activities of signaling proteins (as captured by phosphoproteomic data, for example) have the potential to uncover uncharacterized protein-protein interactions and to identify the subset that are important for cellular response to specific biological stimuli. However, inferring mechanistically plausible protein signaling networks (PSNs) from phosphoproteomics data is a difficult task, owing in part to the lack of sufficiently comprehensive experimental measurements, the inherent limitations of network inference algorithms, and a lack of standards for assessing the accuracy of inferred PSNs. A case study in which 12 research groups inferred PSNs from a phosphoproteomics data set demonstrates an assessment of inferred PSNs on the basis of the accuracy of their predictions. The concurrent prediction of the same previously unreported signaling interactions by different participating teams suggests relevant validation experiments and establishes a framework for combining PSNs inferred by multiple research groups into a composite PSN. We conclude that crowdsourcing the construction of PSNs-that is, outsourcing the task to the interested community-may be an effective strategy for network inference. C1 [Prill, Robert J.; Stolovitzky, Gustavo] IBM Computat Biol Ctr, Yorktown Hts, NY 10598 USA. [Prill, Robert J.; Saez-Rodriguez, Julio] European Bioinformat Inst EMBL EBI, Cambridge CB10 1SD, England. [Saez-Rodriguez, Julio] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany. [Alexopoulos, Leonidas G.] Natl Tech Univ Athens, Dept Mech Engn, Athens 15780, Greece. [Sorger, Peter K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Sorger, Peter K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. C1 [Prill, Robert J.; Stolovitzky, Gustavo] IBM Computat Biol Ctr, Yorktown Hts, NY 10598 USA. [Prill, Robert J.; Saez-Rodriguez, Julio] European Bioinformat Inst EMBL EBI, Cambridge CB10 1SD, England. [Saez-Rodriguez, Julio] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany. [Alexopoulos, Leonidas G.] Natl Tech Univ Athens, Dept Mech Engn, Athens 15780, Greece. [Sorger, Peter K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Sorger, Peter K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. RP Stolovitzky, G (reprint author), IBM Computat Biol Ctr, Yorktown Hts, NY 10598 USA. EM gustavo@us.ibm.com EM gustavo@us.ibm.com RI Saez-Rodriguez, Julio/H-7114-2019 OI Saez-Rodriguez, Julio/0000-0002-8552-8976; Sorger, Peter/0000-0002-3364-1838 FU National Institutes of Health (NIH) through the Columbia University Center for Multiscale Analysis Genomic and Cellular Networks (MAGNet)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS); LINCS [U54HG006097]; [GM68762] FX We acknowledge support for the DREAM project by the National Institutes of Health (NIH) Roadmap Initiative, through the Columbia University Center for Multiscale Analysis Genomic and Cellular Networks (MAGNet), and grant GM68762 for data generation; the LINCS program is currently funding data collection for future DREAM challenges (U54HG006097). CR Alexopoulos LG, 2010, MOL CELL PROTEOMICS, V9, P1849, DOI 10.1074/mcp.M110.000406 Bandura DR, 2009, ANAL CHEM, V81, P6813, DOI 10.1021/ac901049w Bansal M, 2007, MOL SYST BIOL, V3, DOI 10.1038/msb4100120 Bendall SC, 2011, SCIENCE, V332, P687, DOI 10.1126/science.1198704 Ciaccio MF, 2010, NAT METHODS, V7, P148, DOI [10.1038/NMETH.1418, 10.1038/nmeth.1418] Eduati F, 2010, PLOS ONE, V5, DOI 10.1371/journal.pone.0012789 Leclerc RD, 2008, MOL SYST BIOL, V4, DOI 10.1038/msb.2008.52 Ma'ayan A, 2005, SCIENCE, V309, P1078, DOI 10.1126/science.1108876 Ma'ayan A, 2008, P NATL ACAD SCI USA, V105, P19235, DOI 10.1073/pnas.0805344105 Marbach D, 2010, P NATL ACAD SCI USA, V107, P6286, DOI 10.1073/pnas.0913357107 Marbach D, 2009, ANN NY ACAD SCI, V1158, P102, DOI 10.1111/j.1749-6632.2008.03945.x Mitsos A, 2009, PLOS COMPUT BIOL, V5, DOI 10.1371/journal.pcbi.1000591 Morris MK, 2010, BIOCHEMISTRY-US, V49, P3216, DOI 10.1021/bi902202q Nelander S, 2008, MOL SYST BIOL, V4, DOI 10.1038/msb.2008.53 Sachs K, 2005, SCIENCE, V308, P523, DOI 10.1126/science.1105809 Saez-Rodriguez J, 2009, MOL SYST BIOL, V5, DOI 10.1038/msb.2009.87 Stolovitzky G, 2009, ANN NY ACAD SCI, V1158, P159, DOI 10.1111/j.1749-6632.2009.04497.x Wolf-Yadlin A, 2009, CURR OPIN CHEM BIOL, V13, P398, DOI 10.1016/j.cbpa.2009.06.027 NR 18 TC 85 Z9 85 U1 0 U2 18 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD SEP 6 PY 2011 VL 4 IS 189 AR mr7 DI 10.1126/scisignal.2002212 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 816LQ UT WOS:000294601900003 PM 21900204 OA Green Accepted DA 2020-07-01 ER PT J AU Olin, A Henckel, E Chen, Y Lakshmikanth, T Pou, C Mikes, J Gustafsson, A Bernhardsson, AK Zhang, C Bohlin, K Brodin, P AF Olin, Axel Henckel, Ewa Chen, Yang Lakshmikanth, Tadepally Pou, Christian Mikes, Jaromir Gustafsson, Anna Bernhardsson, Anna Karin Zhang, Cheng Bohlin, Kajsa Brodin, Petter TI Stereotypic Immune System Development in Newborn Children SO CELL LA English DT Article ID YELLOW-FEVER VACCINE; MASS CYTOMETRY; T-CELLS; BACTERIAL-INFECTIONS; SUPPRESSOR-CELLS; COLONIZATION; POPULATIONS; MICROBIOTA; RESPONSES; BIOLOGY AB Epidemiological data suggest that early life exposures are key determinants of immune-mediated disease later in life. Young children are also particularly susceptible to infections, warranting more analyses of immune system development early in life. Such analyses mostly have been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. Here, we performed longitudinal analyses in 100 newborn children, sampled up to 4 times during their first 3 months of life. From 100 mu L of blood, we analyze the development of 58 immune cell populations by mass cytometry and 267 plasma proteins by immunoassays, uncovering drastic changes not predictable from cord blood measurements but following a stereotypic pattern. Preterm and term children differ at birth but converge onto a shared trajectory, seemingly driven by microbial interactions and hampered by early gut bacterial dysbiosis. C1 [Olin, Axel; Chen, Yang; Lakshmikanth, Tadepally; Pou, Christian; Mikes, Jaromir; Bernhardsson, Anna Karin; Brodin, Petter] Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, S-17121 Solna, Sweden. [Henckel, Ewa; Gustafsson, Anna; Bohlin, Kajsa] Karolinska Inst, Dept Clin Sci Intervent & Technol, S-14152 Solna, Sweden. [Henckel, Ewa; Gustafsson, Anna; Bernhardsson, Anna Karin; Bohlin, Kajsa; Brodin, Petter] Karolinska Univ Hosp, Dept Neonatol, S-17176 Solna, Sweden. [Zhang, Cheng] KTH, Royal Inst Technol, Sch Biotechnol, Sci Life Lab, S-17121 Stockholm, Sweden. C1 [Olin, Axel; Chen, Yang; Lakshmikanth, Tadepally; Pou, Christian; Mikes, Jaromir; Bernhardsson, Anna Karin; Brodin, Petter] Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, S-17121 Solna, Sweden. [Henckel, Ewa; Gustafsson, Anna; Bohlin, Kajsa] Karolinska Inst, Dept Clin Sci Intervent & Technol, S-14152 Solna, Sweden. [Henckel, Ewa; Gustafsson, Anna; Bernhardsson, Anna Karin; Bohlin, Kajsa; Brodin, Petter] Karolinska Univ Hosp, Dept Neonatol, S-17176 Solna, Sweden. [Zhang, Cheng] KTH, Royal Inst Technol, Sch Biotechnol, Sci Life Lab, S-17121 Stockholm, Sweden. RP Brodin, P (reprint author), Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, S-17121 Solna, Sweden.; Brodin, P (reprint author), Karolinska Univ Hosp, Dept Neonatol, S-17176 Solna, Sweden. EM petter.brodin@ki.se EM petter.brodin@ki.se RI Brodin, Petter/C-3317-2011; Mikes, Jaromir/X-3588-2019; Henckel, Ewa/AAD-3185-2019; Zhang, Cheng/L-7906-2016; Tadepally, Lakshmikanth/P-5154-2019 OI Brodin, Petter/0000-0002-8103-0046; Mikes, Jaromir/0000-0002-9941-7855; Zhang, Cheng/0000-0002-3721-8586; Tadepally, Lakshmikanth/0000-0001-7256-5770; Olin, Axel/0000-0002-1161-4476; Henckel, Ewa/0000-0003-0775-1563 FU ERCEuropean Research Council (ERC) [StG-677559]; Swedish Research Council,Swedish Research Council; Karolinska InstitutetKarolinska Institutet; Swedish Society for Medical Research FX We thank all families for their participation and nurses, midwives, and physicians for help with sample collection. We thank Jochen Schwenk and Ragna ussler at the SciLifeLab Plasma profiling platform and Lars Engstrand and Luisa Hugerth at the Clinical Genomics Facility for help with 16S rRNA profiling. P.B. is grateful to Professor Mark Davis of Stanford University for his valuable mentorship. This study was supported by an ERC Starting Grant (StG-677559), the Swedish Research Council, Karolinska Institutet, and the Swedish Society for Medical Research. 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Poidinger, Michael Chen, Jinmiao TI Cytofkit: A Bioconductor Package for an Integrated Mass Cytometry Data Analysis Pipeline SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID CELL; PROGRESSION AB Single-cell mass cytometry significantly increases the dimensionality of cytometry analysis as compared to fluorescence flow cytometry, providing unprecedented resolution of cellular diversity in tissues. However, analysis and interpretation of these high-dimensional data poses a significant technical challenge. Here, we present cytofkit, a new Bioconductor package, which integrates both state-of-the-art bioinformatics methods and in-house novel algorithms to offer a comprehensive toolset for mass cytometry data analysis. Cytofkit provides functions for data pre-processing, data visualization through linear or non-linear dimensionality reduction, automatic identification of cell subsets, and inference of the relatedness between cell subsets. This pipeline also provides a graphical user interface (GUI) for ease of use, as well as a shiny application (APP) for interactive visualization of cell subpopulations and progression profiles of key markers. Applied to a CD14(-)CD19(-) PBMCs dataset, cytofkit accurately identified different subsets of lymphocytes; applied to a human CD4(+) T cell dataset, cytofkit uncovered multiple subtypes of TFH cells spanning blood and tonsils. Cytofkit is implemented in R, licensed under the Artistic license 2.0, and freely available from the Bioconductor website, https://bioconductor.org/packages/cytofkit/. Cytofkit is also applicable for flow cytometry data analysis. C1 [Chen, Hao; Lau, Mai Chan; Wong, Michael Thomas; Newell, Evan W.; Poidinger, Michael; Chen, Jinmiao] ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore. C1 [Chen, Hao; Lau, Mai Chan; Wong, Michael Thomas; Newell, Evan W.; Poidinger, Michael; Chen, Jinmiao] ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore. RP Chen, JM (reprint author), ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore. EM chen_jinmiao@immunol.a-star.edu.sg EM chen_jinmiao@immunol.a-star.edu.sg RI Newell, Evan/AAE-9470-2020; Newell, Evan W/F-9711-2012; Lau, Mai Chan/L-5186-2019 OI Newell, Evan/0000-0002-2889-243X; Newell, Evan W/0000-0002-2889-243X; chen, jinmiao/0000-0001-7547-6423; Poidinger, Michael/0000-0002-1047-2277 FU A-STAR/SIgNAgency for Science Technology & Research (ASTAR) FX This study was funded by A-STAR/SIgN core funding (JC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 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Biotechnol. PD FEB PY 2014 VL 32 IS 2 BP 149 EP 157 DI 10.1038/nbt.2783 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AA4NY UT WOS:000331074000020 PM 24441473 OA Green Accepted DA 2020-07-01 ER PT J AU Strauss-Albee, DM Fukuyama, J Liang, EC Yao, Y Jarrell, JA Drake, AL Kinuthia, J Montgomery, RR John-Stewart, G Holmes, S Blish, CA AF Strauss-Albee, Dara M. Fukuyama, Julia Liang, Emily C. Yao, Yi Jarrell, Justin A. Drake, Alison L. Kinuthia, John Montgomery, Ruth R. John-Stewart, Grace Holmes, Susan Blish, Catherine A. TI Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NATURAL-KILLER-CELLS; NILE VIRUS-INFECTION; MASS CYTOMETRY; HIV ACQUISITION; CUTTING EDGE; T-CELLS; EXPRESSION; RESPONSES; INNATE; CYTOMEGALOVIRUS AB Innate natural killer (NK) cells are diverse at the single-cell level because of variegated expressions of activating and inhibitory receptors, yet the developmental roots and functional consequences of this diversity remain unknown. Because NK cells are critical for antiviral and antitumor responses, a better understanding of their diversity could lead to an improved ability to harness them therapeutically. We found that NK diversity is lower at birth than in adults. During an antiviral response to either HIV-1 or West Nile virus, NK diversity increases, resulting in terminal differentiation and cytokine production at the cost of cell division and degranulation. In African women matched for HIV-1 exposure risk, high NK diversity is associated with increased risk of HIV-1 acquisition. Existing diversity may therefore decrease the flexibility of the antiviral response. Collectively, the data reveal that human NK diversity is a previously undefined metric of immune history and function that may be clinically useful in forecasting the outcomes of infection and malignancy. C1 [Strauss-Albee, Dara M.; Jarrell, Justin A.; Blish, Catherine A.] Stanford Univ, Sch Med, Stanford Immunol, Stanford, CA 94305 USA. [Strauss-Albee, Dara M.; Liang, Emily C.; Jarrell, Justin A.; Blish, Catherine A.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Fukuyama, Julia; Holmes, Susan] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Yao, Yi; Montgomery, Ruth R.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06519 USA. [Drake, Alison L.; John-Stewart, Grace] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Kinuthia, John] Kenyatta Natl Hosp, Dept Res & Programs, Nairobi 00202, Kenya. [John-Stewart, Grace] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [John-Stewart, Grace] Univ Washington, Dept Med, Seattle, WA 98195 USA. [John-Stewart, Grace] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. C1 [Strauss-Albee, Dara M.; Jarrell, Justin A.; Blish, Catherine A.] Stanford Univ, Sch Med, Stanford Immunol, Stanford, CA 94305 USA. [Strauss-Albee, Dara M.; Liang, Emily C.; Jarrell, Justin A.; Blish, Catherine A.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Fukuyama, Julia; Holmes, Susan] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. [Yao, Yi; Montgomery, Ruth R.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06519 USA. [Drake, Alison L.; John-Stewart, Grace] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Kinuthia, John] Kenyatta Natl Hosp, Dept Res & Programs, Nairobi 00202, Kenya. [John-Stewart, Grace] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [John-Stewart, Grace] Univ Washington, Dept Med, Seattle, WA 98195 USA. [John-Stewart, Grace] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. RP Blish, CA (reprint author), Stanford Univ, Sch Med, Stanford Immunol, Stanford, CA 94305 USA. EM cblish@stanford.edu EM cblish@stanford.edu OI Blish, Catherine/0000-0001-6946-7627; John-Stewart, Grace/0000-0002-4301-1573; Holmes, Susan/0000-0002-2208-8168; Montgomery, Ruth/0000-0002-8661-4454 FU National Science FoundationNational Science Foundation (NSF) [DGE-114740]; Ruth L. Kirschstein National Research Service AwardUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1F31AI118469-01]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U19AI089992, DP2AI11219301, P01 HSD 064915]; Beckman Young Investigator Award; California HIV Research Program IDEA award; University of Washington Center for AIDS Research [P30 AI27757] FX Funding for this work was provided by National Science Foundation training grant DGE-114740 (D.M.S.-A.), Ruth L. Kirschstein National Research Service Award 1F31AI118469-01 (D.M.S.-A.), NIH Award U19AI089992 (R.R.M.), a Beckman Young Investigator Award (C.A.B.), a California HIV Research Program IDEA award (C.A.B.), and NIH Directors' New Innovator Award DP2AI11219301 (C.A.B.). The Kenyan studies were funded by NIH (P01 HSD 064915) and received assistance from the University of Washington Center for AIDS Research (P30 AI27757). 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PD OCT PY 2015 VL 31 IS 10 SI SI BP 576 EP 586 DI 10.1016/j.tig.2015.07.003 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA CU2JN UT WOS:000363349900005 PM 26450340 OA Green Accepted DA 2020-07-01 ER PT J AU Diggins, KE Ferrell, PB Irish, JM AF Diggins, Kirsten E. Ferrell, P. Brent, Jr. Irish, Jonathan M. TI Methods for discovery and characterization of cell subsets in high dimensional mass cytometry data SO METHODS LA English DT Article DE Mass cytometry; Flow cytometry; Single cell biology; Unsupervised analysis; Machine learning ID FLOW-CYTOMETRY; AUTOMATED IDENTIFICATION; CLASSIFICATION; EXPRESSION; REDUCTION; NETWORKS; IMMUNE AB The flood of high-dimensional data resulting from mass cytometry experiments that measure more than 40 features of individual cells has stimulated creation of new single cell computational biology tools. These tools draw on advances in the field of machine learning to capture multi-parametric relationships and reveal cells that are easily overlooked in traditional analysis. Here, we introduce a workflow for high dimensional mass cytometry data that emphasizes unsupervised approaches and visualizes data in both single cell and population level views. This workflow includes three central components that are common across mass cytometty analysis approaches: (1) distinguishing initial populations, (2) revealing cell subsets, and (3) characterizing subset features. In the implementation described here, viSNE, SPADE, and heatmaps were used sequentially to comprehensively characterize and compare healthy and malignant human tissue samples. The use of multiple methods helps provide a comprehensive view of results, and the largely unsupervised workflow facilitates automation and helps researchers avoid missing cell populations with unusual or unexpected phenotypes. Together, these methods develop a framework for future machine learning of cell identity. (C) 2015 Elsevier Inc. All rights reserved. C1 [Diggins, Kirsten E.; Irish, Jonathan M.] Vanderbilt Univ, Sch Med, Canc Biol, Nashville, TN 37232 USA. [Ferrell, P. Brent, Jr.] Vanderbilt Univ, Sch Med, Med Div Hematol Oncol, Nashville, TN 37232 USA. [Irish, Jonathan M.] Vanderbilt Univ, Sch Med, Pathol Microbiol & Immunol, Nashville, TN 37232 USA. C1 [Diggins, Kirsten E.; Irish, Jonathan M.] Vanderbilt Univ, Sch Med, Canc Biol, Nashville, TN 37232 USA. [Ferrell, P. Brent, Jr.] Vanderbilt Univ, Sch Med, Med Div Hematol Oncol, Nashville, TN 37232 USA. [Irish, Jonathan M.] Vanderbilt Univ, Sch Med, Pathol Microbiol & Immunol, Nashville, TN 37232 USA. RP Irish, JM (reprint author), Vanderbilt Univ, Sch Med, 740B Preston Bldg,2220 Pierce Ave, Nashville, TN 37232 USA. EM jonathan.irish@vanderbilt.edu EM jonathan.irish@vanderbilt.edu RI Irish, Jonathan M/E-1180-2013; Diggins, Kirsten/F-7348-2015 OI Irish, Jonathan M/0000-0001-9428-8866; Ferrell, Paul/0000-0003-1140-9154; Diggins, Kirsten/0000-0003-1622-0158 FU Vanderbilt-Ingram Cancer Center (VICC) [P30 CA68485]; VICC Young Ambassadors award; VICC Hematology Helping Hands award; NIH/NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [K12 CA090625]; [R25 CA136440-04] FX This study was supported by R25 CA136440-04 (K.E.D.), NIH/NCI K12 CA090625 (P.B.F.), R00 CA143231-03 (J.M.I.), the Vanderbilt-Ingram Cancer Center (VICC, P30 CA68485), and VICC Young Ambassadors and VICC Hematology Helping Hands awards. Thanks to Mikael Roussel for helpful discussions of myeloid cell identity markers. 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TI Chikungunya Viral Arthritis in the United States A Mimic of Seronegative Rheumatoid Arthritis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID WESTERN-HEMISPHERE; VIRUS; DISEASE; SPREAD AB Objective. Chikungunya virus (CHIKV) is an arthritogenic mosquito-transmitted alphavirus that spread to the Caribbean in 2013 and to the US in 2014. CHIKV-infected patients develop inflammatory arthritis that can persist for months or years, but little is known about the rheumatologic and immunologic features of CHIKV-related arthritis in humans, particularly as compared to rheumatoid arthritis (RA). The purpose of this study was to describe these features in a group of 10 American travelers who were nearly simultaneously infected while visiting Haiti in June 2014. Methods. Patient history was obtained and physical examination and laboratory tests were performed. All patients with CHIKV-related arthritis had detectable levels of anti-CHIKV IgG. Using cytometry by time-of-flight (CyTOF), we analyzed peripheral blood mononuclear cells in CHIKV-infected patients, healthy controls, and patients with untreated, active RA. Results. Among 10 CHIKV-infected individuals, 8 developed persistent symmetric polyarthritis that met the American College of Rheumatology/European League Against Rheumatism 2010 criteria for (seronegative) RA. CyTOF analysis revealed that RA and CHIKV-infected patients had greater percentages of activated and effector CD4+ and CD8+ T cells than healthy controls. Conclusion. In addition to similar clinical features, patients with CHIKV infection and patients with RA develop very similar peripheral T cell phenotypes. These overlapping clinical and immunologic features highlight a need for rheumatologists to consider CHIKV infection when evaluating patients with new, symmetric polyarthritis. C1 [Miner, Jonathan J.; Yeang, Han Xian Aw; Fox, Julie M.; Taffner, Samantha; Malkova, Olga N.; Oh, Stephen T.; Kim, Alfred H. J.; Diamond, Michael S.; Lenschow, Deborah J.; Yokoyama, Wayne M.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Yokoyama, Wayne M.] Howard Hughes Med Inst, Chevy Chase, MD USA. C1 [Miner, Jonathan J.; Yeang, Han Xian Aw; Fox, Julie M.; Taffner, Samantha; Malkova, Olga N.; Oh, Stephen T.; Kim, Alfred H. J.; Diamond, Michael S.; Lenschow, Deborah J.; Yokoyama, Wayne M.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Yokoyama, Wayne M.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Yokoyama, WM (reprint author), Washington Univ, Sch Med, Div Rheumatol, Campus Box 8045, St Louis, MO 63110 USA. EM yokoyama@wustl.edu EM yokoyama@wustl.edu RI Diamond, Michael/AAH-1733-2019; Kim, Alfred H.J./F-5699-2013 OI Diamond, Michael/0000-0002-8791-3165; Kim, Alfred H.J./0000-0003-4074-0516; Fox, Julie/0000-0003-0567-738X FU Barnes-Jewish Hospital Foundation; Howard Hughes Medical InstituteHoward Hughes Medical Institute; Center for Human Immunology and Immunotherapy Programs at Washington University; NIH (Rhematic Diseases Core Center) [P30-AR-048335]; PfizerPfizer; JanssenJohnson & Johnson USAJanssen Biotech Inc; AmgenAmgen; InBios; MerckMerck & Company FX Supported by the Barnes-Jewish Hospital Foundation, the Howard Hughes Medical Institute, the Center for Human Immunology and Immunotherapy Programs at Washington University, and the NIH (Rhematic Diseases Core Center grant P30-AR-048335).; Dr. Kim has received consulting fees, speaking fees, and/or honoraria from Pfizer, Janssen, and Amgen (less than $10,000 each). 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