Dissecting CD8+ T cell pathology of severe SARS-CoV-2 infection by single-cell immunoprofiling

Front Immunol. 2022 Dec 16:13:1066176. doi: 10.3389/fimmu.2022.1066176. eCollection 2022.


Introduction: 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.

Methods: 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.

Results: We observed increased CD8+ T cell exhaustion 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.

Discussion: 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.

Keywords: CD16; CD8+ T cells; FCGR3A; NK-like T cell; SARS-CoV-2; immunoprofiling; scRNA-seq; scTCR-seq.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies
  • CD8-Positive T-Lymphocytes*
  • COVID-19*
  • Humans
  • SARS-CoV-2


  • Antibodies

Supplementary concepts

  • SARS-CoV-2 variants