Published September 30, 2022 | Version v1
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Dissecting CD8+ T cell pathology of severe SARS-CoV-2 infection by single-cell immunoprofiling

Authors/Creators

  • 1. Institute of Experimental Medicine and Systems Biology, University Hospital RWTH Aachen, Germany
  • 2. Institute for Computational Genomics, University Hospital RWTH Aachen
  • 3. Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany
  • 4. Institute of Human Genetics, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany
  • 5. Institute of Medical Microbiology, RWTH University Hospital Aachen, Aachen, Germany
  • 6. Department of Medicine, St Antonius Hospital, Eschweiler, Germany
  • 7. Institute for Occupational, Social and Environmental Medicine, University Hospital RWTH Aachen
  • 8. Institute for Transplantation Diagnostics and Cell Therapeutics, University Hospital Düsseldorf, Düsseldorf, Germany
  • 9. Department of Cardiology, Angiology and Intensive Care Medicine, University Hospital RWTH Aachen
  • 10. Institute of Experimental Immunology, University of Bonn, Germany
  • 11. Department of Intensive and Intermediate Care, University Hospital RWTH Aachen
  • 12. Department of Pneumology and Intensive Care Medicine, University Hospital RWTH Aachen
  • 13. Department of Cell Biology, RWTH Aachen University

Description

SARS-CoV-2 infection results in varying disease severity, ranging from asymptomatic infection to severe illness. A detailed understanding of the immune response to SARS-CoV-2 is critical to unravel the causative factors underlying differences in disease severity and to develop optimal vaccines against new SARS-CoV-2 variants. We combined single-cell RNA and T cell receptor sequencing with CITE-seq antibodies to characterize the CD8+ T cell response to SARS-CoV-2 infection at high resolution and compared responses between mild and severe COVID-19. We observed a population of exhausted CD8+ T cells in severe SARS-CoV-2 infection and identified a population of NK-like, terminally differentiated CD8+ effector T cells characterized by expression of FCGR3A (encoding CD16). Further characterization of NK-like CD8+ T cells revealed heterogeneity among CD16+ NK-like CD8+ T cells and profound differences in cytotoxicity, exhaustion, and NK-like differentiation between mild and severe disease conditions. We propose a model in which differences in the surrounding inflammatory milieu lead to crucial differences in NK-like differentiation of CD8+ effector T cells, ultimately resulting in the appearance of NK-like CD8+ T cell populations of different functionality and pathogenicity. Our in-depth characterization of the CD8+ T cell-mediated response to SARS-CoV-2 infection provides a basis for further investigation of the importance of NK-like CD8+ T cells in COVID-19 severity.

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