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

2021; American Association for the Advancement of Science; Volume: 6; Issue: 57 Linguagem: Inglês

10.1126/sciimmunol.abg6461

2470-9468

Benedikt Agerer, Maximilian Koblischke, Venugopal Gudipati, Luis F. 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 E. Shaw, Alexander Lercher, Pia Gattinger, Ricard Torralba-Gombau, Doris Trapin, Thomas Penz, Daniele Barreca, Ingrid Faé, S. 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,

Immunotherapy and Immune Responses

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.