Antigen-specific memory NK cell responses against HIV and influenza utilize the NKG2/HLA-E axis
Authors/Creators
- 1. Beth Israel Deaconess Medical Center
- 2. Ragon Institute*
- 3. Heinrich Pette Institute*
- 4. Institut Pasteur
- 5. University of Alabama at Birmingham
- 6. Duke University School of Medicine
Description
For over a decade, multiple studies have disputed the notion of natural killer (NK) cells as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including two critical global health priorities – human immunodeficiency virus (HIV) and influenza. However, the mechanisms underlying antigen specificity remain unknown. Herein, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism largely dependent on the activating CD94/NKG2C receptor and its ligand HLA-E, and confirm these findings by three rigorous assays. We validated the permanent acquisition of antigen-specificity by individual memory NK cells by single-cell cloning. We identified biomarkers of antigen-specific NK cell memory through complex immunophenotyping by 30-parameter flow cytometry showing elevated expression of KLRG1, a4b7, and NKG2C. Finally, we show individual HLA-E-restricted peptides that may constitute the dominant NK cell response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms behind antigen-specific memory NK cell responses, and suggest they could be targeted for future vaccines, cure strategies, or other therapeutic interventions.
Notes
Funding provided by: National Institutes of Health
ROR ID: https://ror.org/01cwqze88
Award Number: R01AI116363
Funding provided by: National Institutes of Health
ROR ID: https://ror.org/01cwqze88
Award Number: R21AI137835
Funding provided by: National Institutes of Health
ROR ID: https://ror.org/01cwqze88
Award Number: R01AI158516
Funding provided by: National Institutes of Health
ROR ID: https://ror.org/01cwqze88
Award Number: R01AI120828
Funding provided by: National Institutes of Health
ROR ID: https://ror.org/01cwqze88
Award Number: R01AI143457
Funding provided by: National Institutes of Health
ROR ID: https://ror.org/01cwqze88
Award Number: R01AI161010
Funding provided by: National Institutes of Health
ROR ID: https://ror.org/01cwqze88
Award Number: UM1 AI164570
Funding provided by: National Institutes of Health
ROR ID: https://ror.org/01cwqze88
Award Number: P01AI162242
Funding provided by: National Institutes of Health
ROR ID: https://ror.org/01cwqze88
Award Number: UM1 AI164570
Funding provided by: University of Alabama at Birmingham
ROR ID: https://ror.org/008s83205
Award Number: P30 AI060354
Funding provided by: National Institutes of Health
ROR ID: https://ror.org/01cwqze88
Award Number: P01AI162242
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