Recruitment of highly functional SARS-CoV-2-specific CD8+ T cell receptors mediating cytotoxicity of virus-infected target cells in non-severe COVID-19

Wagner, K. I.; Mateyka, L. M.; Jarosch, S.; Grass, V.; Weber, S.; Schober, K.; Hammel, M.; Burrell, T.; Kalali, B.; Poppert, H.; Beyer, H.; Schambeck, S.; Holdenrieder, S.; Stroetges-Achatz, A.; Haselmann, V.; Neumaier, M.; Erber, J.; Priller, A.; Yazici, S.; Roggendorf, H.; Odendahl, M.; Tonn, T.; Witter, K.; Dick, A.; Mijocevic, H.; Protzer, U.; Knolle, P. A.; Pichlmair, A.; Crowell, C. S.; Gerhard, M.; D Ippolito, E.; Busch, D. H.

T cell immunity is crucial for the control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and has been widely characterized on a quantitative level. In contrast, the quality of such T cell responses has been poorly investigated, in particular in the case of CD8+ T cells. Here, we explored the quality of SARS-CoV-2-specific CD8+ T cell responses in individuals who recovered from mild symptomatic infections, through which protective immunity should develop, by functional characterization of their T cell receptor (TCR) repertoire. CD8+ T cell responses specific for SARS-CoV-2-derived epitopes were low in frequency but could be detected robustly early as well as late - up to twelve months - after infection. A pool of immunodominant epitopes, which accurately identified previous SARSCoV- 2 infections, was used to isolate TCRs specific for epitopes restricted by common HLA class I molecules. TCR-engineered T cells showed heterogeneous functional avidity and cytotoxicity towards virus-infected target cells. High TCR functionality correlated with gene signatures of T cell function and activation that, remarkably, could be retrieved for each epitope:HLA combination and patient analyzed. Overall, our data demonstrate that highly functional HLA class I TCRs are recruited and maintained upon mild SARS-CoV-2 infection. Such validated epitopes and TCRs could become valuable tools for the development of diagnostic tests determining the quality of SARS-CoV-2-specific CD8+ T cell immunity, and thereby investigating correlates of protection, as well as to restore functional immunity through therapeutic transfer of TCR-engineered T cells.