Dissecting CD8+ T cell pathology of severe SARS-CoV-2 infection by single-cell epitope mapping

Schreibing, Felix; Hannani, Monica; Ticconi, Fabio; Fewings, Eleanor; Nagai, James S; Begemann, Matthias; Kuppe, Christoph; Kurth, Ingo; Kranz, Jennifer; Frank, Dario; Anslinger, Teresa M; Ziegler, Patrick; Kraus, Thomas; Enczmann, Jürgen; Balz, Vera; Windhofer, Frank; Balfanz, Paul; Kurts, Christian; Marx, Gernot; Marx, Nikolaus; Dreher, Michael; Schneider, Rebekka K; Saez-Rodriguez, Julio; Costa, Ivan; Kramann, Rafael

The current COVID-19 pandemic represents a global challenge. A better understanding of the immune response against SARS-CoV-2 is key to unveil the differences in disease severity and to develop future vaccines targeting novel SARS-CoV-2 variants. Feature barcode technology combined with CITE-seq antibodies and DNA-barcoded peptide-MHC I Dextramer reagents enabled us to identify relevant SARS-CoV-2-derived epitopes and compare epitope-specific CD8+ T cell populations between mild and severe COVID-19. We identified a strong CD8+ T cell response against an S protein-derived epitope. CD8+ effector cells in severe COVID-19 displayed hyperactivation, T cell exhaustion and were missing characteristics of long-lived memory T cells. We identify A*0101 WTAGAAAYY as an immunogenic CD8+ T cell epitope with the ability to drive clonal expansion. We provide an in-depth characterization of the CD8+ T cell-mediated response to SARS-CoV-2 infection which will be relevant for the development of molecular and targeted therapies and potential adjustments of vaccination strategies.