Profiling CD8+ T cell epitopes of COVID-19 convalescents reveals reduced cellular immune responses to SARS-CoV-2 variants

Cellular immunity is important in determining the disease severity of COVID-19 patients. However, current understanding of SARS-CoV-2 epitopes mediating cellular immunity is limited. Here we apply T-Scan, a recently developed method, to identifyCD8(+) T cell epitopes fromCOVID-19 patients of four majorHLA-A alleles. Several identified epitopes are conserved across human coronaviruses, which might mediate pre-existing cellular immunity to SARS-CoV-2. In addition, we identify and validate four epitopes that were mutated in the newly circulating variants, including the Delta variant. The mutations significantly reduce T cell responses to the epitope peptides in convalescent and vaccinated samples. We further determine the crystal structure of HLAA*02:01/HLA-A*24:02 in complex with the epitope KIA_S/NYN_S, respectively, which reveals the importance of K417 and L452 of the spike protein for binding to HLA. Our data suggest that evading cellular immunity might contribute tothe increased transmissibilityand disease severity associated with thenewSARS-CoV-2 variants.

Automated summary

Cellular immunity plays a crucial role in determining the disease severity of COVID-19 patients. Identified epitopes from SARS-CoV-2 are conserved across human coronaviruses, suggesting a potential pre-existing cellular immunity. Mutations in newly circulating variants reduce T cell responses to epitopes, indicating a possible evasion of cellular immunity.