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

Benedikt Agerer, Maximilian Koblischke, Venugopal Gudipati, Luis Fernando Montaño-Gutierrez, Mark Smyth, Alexandra Popa, Jakob-Wendelin Genger, Lukas Endler, David M Florian, Vanessa Mühlgrabner, Marianne Graninger, Stephan W Aberle, Anna-Maria Husa, Lisa Ellen Shaw, Alexander Lercher, Pia Gattinger, Ricard Torralba-Gombau, Doris Trapin, Thomas Penz, Daniele BarrecaIngrid Fae, Sabine Wenda, Marianna Traugott, Gernot Walder, Winfried F Pickl, Volker Thiel, Franz Allerberger, Hannes Stockinger, Elisabeth Puchhammer-Stöckl, Wolfgang Weninger, Gottfried Fischer, Wolfgang Hoepler, Erich Pawelka, Alexander Zoufaly, Rudolf Valenta, Christoph Bock, Wolfgang Paster, René Geyeregger, Matthias Farlik, Florian Halbritter, Johannes B Huppa, Judith H Aberle, Andreas Bergthaler

Research output: Journal article (peer-reviewed)Journal article

108 Citations (Scopus)


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.

Original languageEnglish
Article numberabg6461
JournalScience immunology
Issue number57
Publication statusPublished - 25 Mar 2021


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


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