Identification of Cross-Reactive CD8⁺ T Cell Receptors with High Functional Avidity to a SARS-CoV-2 Immunodominant Epitope and Its Natural Mutant Variants

ABSTRACT

Despite the growing knowledge of T cell responses and their epitopes in COVID-19 patients, there is a lack of detailed characterizations for T cell-antigen interactions and T cell functions. Using a peptide library predicted with HLA class I-restriction, specific CD8⁺ T cell responses were identified in over 75% of COVID-19 convalescent patients. Among the 15 SARS-CoV-2 epitopes identified from the S and N proteins, N^361-369 (KTFPPTEPK) was the most dominant epitope. Importantly, we discovered 2 N^361-369-specific T cell receptors (TCRs) with high functional avidity, and they exhibited complementary cross-reactivity to reported N^361-369 mutant variants. In dendritic cells (DCs) and the lung organoid model, we found that the N^361-369 epitope could be processed and endogenously presented to elicit the activation and cytotoxicity of CD8⁺ T cells ex vivo. Our study evidenced potential mechanisms of cellular immunity to SARS-CoV-2, illuminating natural ways of viral clearance with high relevancy in the vaccine development.