Nonconserved epitopes dominate reverse preexisting T cell immunity in COVID-19 convalescents

The herd immunity against SARS-CoV-2 is continuously consolidated across the world during the ongoing pandemic.However,the potential function of the nonconserved epitopes in the reverse preexisting cross-reactivity induced by SARS-CoV-2 to other human coronaviruses is not well explored.In our research,we assessed T cell responses to both conserved and nonconserved peptides shared by SARS-CoV-2 and SARS-CoV,identifying cross-reactive CD8^(+)T cell epitopes using enzyme-linked immunospot and intracellular cytokine staining assays.Then,in vitro refolding and circular dichroism were performed to evaluate the thermal stability of the HLA/peptide complexes.Lastly,single-cell T cell receptor reservoir was analyzed based on tetramer staining.Here,we discovered that cross-reactive T cells targeting SARS-CoV were present in individuals who had recovered from COVID-19,and identified SARS-CoV-2 CD8^(+)T cell epitopes spanning the major structural antigens.T cell responses induced by the nonconserved peptides between SARS-CoV-2 and SARS-CoV were higher and played a dominant role in the cross-reactivity in COVID-19 convalescents.Cross-T cell reactivity was also observed within the identified series of CD8^(+)T cell epitopes.For representative immunodominant peptide pairs,although the HLA binding capacities for peptides from SARS-CoV-2 and SARS-CoV were similar,the TCR repertoires recognizing these peptides were distinct.Our results could provide beneficial information for the development of peptide-based universal vaccines against coronaviruses.