SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8 + T cell responses

Sci Immunol. 2021 Mar 4;6(57):eabg6461. doi: 10.1126/sciimmunol.abg6461.

Abstract

CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8+ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • COVID-19* / genetics
  • COVID-19* / immunology
  • COVID-19* / pathology
  • Cell Proliferation
  • Epitopes, T-Lymphocyte* / genetics
  • Epitopes, T-Lymphocyte* / immunology
  • HLA-A Antigens / immunology*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunity, Cellular*
  • Interferon-gamma / immunology
  • Mutation*
  • Peptides / genetics
  • Peptides / immunology
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / immunology

Substances

  • Epitopes, T-Lymphocyte
  • HLA-A Antigens
  • IFNG protein, human
  • Peptides
  • Interferon-gamma