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

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

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.