SARS-CoV-2 mutations affect antigen processing by the proteasome to alter CD8 + T cell responses.

Mutations within viral epitopes can result in escape from T cells, but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two SARS-CoV-2 nucleoprotein CD8 epitopes, we investigated the contribution of these flanking mutations to proteasomal processing and T cell activation. We found decreased NP-B*27:05 CD8 T cell responses to the NP-Q7K mutation, likely due to a lack of efficient epitope production by the proteasome, suggesting immune escape caused by this mutation. In contrast, NP-P6L and NP-D103 N/Y mutations flanking the NP-B*27:05 and NP-B*07:02 epitopes, respectively, increased CD8 T cell responses associated with enhanced epitope production by the proteasome. Our results provide evidence that SARS-CoV-2 mutations outside the epitope could have a significant impact on proteasomal processing, either contributing to T cell escape or enhancement that may be exploited for future vaccine design.