Ex vivo detection of SARS-CoV-2-specific CD8+ T cells: rapid induction, prolonged contraction, and formation of functional memory

Schulien, Isabel; Kemming, Janine; Oberhardt, Valerie; Wild, Katharina; Seidel, Lea M.; Killmer, Saskia; Sagar,; Daul, Franziska; Lago, Marilyn Salvat; Decker, Annegrit; Luxenburger, Hendrik; Binder, Benedikt; Bettinger, Dominik; Sogukpinar, Oezlem; Rieg, Siegbert; Panning, Marcus; Huzly, Daniela; Schwemmle, Martin; Kochs, Georg; Waller, Cornelius F.; Nieters, Alexandra; Duerschmied, Daniel; Emmerich, Florian; Mei, Henrik; Schulz, Axel; Llewellyn-Lacey, Sian; Price, David A.; Boettler, Tobias; Bengsch, Bertram; Thimme, Robert; Hofmann, Maike; Neumann-Haefelin, Christoph

CD8+ T cells are critical for the elimination and long-lasting protection of many viral infections, but their role in the current SARS-CoV-2 pandemic is unclear. Emerging data indicates that SARS-CoV-2-specific CD8+ T cells are detectable in the majority of individuals recovering from SARS-CoV-2 infection. However, optimal virus-specific epitopes, the role of pre-existing heterologous immunity as well as their kinetics and differentiation program during disease control have not been defined in detail. Here, we show that both pre-existing and newly induced SARS-CoV-2-specific CD8+ T-cell responses are potentially important determinants of immune protection in mild SARS-CoV-2 infection. In particular, our results can be summarized as follows: First, immunodominant SARS-CoV-2-specific CD8+ T-cell epitopes are targeted in the majority of individuals with convalescent SARS-CoV-2 infection. Second, MHC class I tetramer analyses revealed the emergence of phenotypically diverse and functionally competent pre-existing and newly induced SARS-CoV-2-specific memory CD8+ T cells that showed similar characteristics compared to influenza-specific CD8+ T cells. Third, SARS-CoV-2-specific CD8+ T-cell responses are more robustly detectable than antibodies against the SARS-CoV-2-spike protein. This was confirmed in a longitudinal analysis of acute-resolving infection that demonstrated rapid induction of the SARS-CoV-2-specific CD8+ T cells within a week followed by a prolonged contraction phase that outlasted the waning humoral immune response indicating that CD8+ T-cell responses might serve as a more precise correlate of antiviral immunity than antibody measurements after convalescence. Collectively, these data provide new insights into the fine specificity, heterogeneity, and dynamics of SARS-CoV-2-specific memory CD8+ T cells, potentially informing the rational development of a protective vaccine against SARS-CoV-2.