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

Benedikt Agerer1Maximilian Koblischke2Venugopal Gudipati3Luis Fernando Montaño-Gutierrez4Mark Smyth1Alexandra Popa1Jakob-Wendelin Genger1Lukas Endler1David M Florian2Vanessa Mühlgrabner3Marianne Graninger2Stephan W Aberle2Anna-Maria Husa4Lisa Ellen Shaw5Alexander Lercher1Pia Gattinger6Ricard Torralba-Gombau1Doris Trapin7Thomas Penz1Daniele Barreca1Ingrid Fae8Sabine Wenda8Marianna Traugott9Gernot Walder10Winfried F Pickl711Volker Thiel1213Franz Allerberger14Hannes Stockinger3Elisabeth Puchhammer-Stöckl2Wolfgang Weninger5Gottfried Fischer7Wolfgang Hoepler9Erich Pawelka8Alexander Zoufaly8Rudolf Valenta36111516Christoph Bock117Wolfgang Paster4René Geyeregger4Matthias Farlik5Florian Halbritter4Johannes B Huppa3Judith H Aberle2Andreas Bergthaler18

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

AbstractCD8+ 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.

Links: PMID: 33664060; DOI: 10.1126/sciimmunol.abg6461

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