SARS-CoV-2 genome-wide T cell epitope mapping reveals immunodominance and substantial CD8+ T cell activation in COVID-19 patients

T cells are important for effective viral clearance, elimination of virus-infected cells, and long-term disease protection. To examine the full spectrum of CD8(+) T cell immunity in COVID-19, we experimentally evaluated 3141 major histocompatibility complex (MHC) class I-binding peptides covering the complete SARS-CoV-2 genome. Using DNA-barcoded peptide-MHC complex multimers combined with a T cell phenotype panel, we report a comprehensive list of 122 immunogenic and a subset of immunodominant SARS-CoV-2 T cell epitopes. Substantial CD8(+) T cell recognition was observed in patients with COVID-19, with up to 27% of all CD8(+) lymphocytes interacting with SARS-CoV-2-derived epitopes. Most immunogenic regions were derived from open reading frame 1 (ORF1) and ORF3, with ORF1 containing most of the immunodominant epitopes. CD8(+) T cell recognition of lower affinity was also observed in healthy donors toward SARS-CoV-2-derived epitopes. This preexisting T cell recognition signature was partially overlapping with the epitope landscape observed in patients with COVID-19 and may drive the further expansion of T cell responses to SARS-CoV-2 infection. The phenotype of the SARS-CoV-2-specific CD8(+) T cells revealed a strong T cell activation in patients with COVID-19, whereas minimal T cell activation was seen in healthy individuals. We found that patients with severe disease displayed significantly larger SARS-CoV-2-specific T cell populations compared with patients with mild diseases, and these T cells displayed a robust activation profile. These results further our understanding of T cell immunity to SARS-CoV-2 infection and hypothesize that strong antigen-specific T cell responses are associated with different disease outcomes.

Automated summary

This study experimentally evaluated MHC class I-binding peptides covering the complete SARS-CoV-2 genome, revealing significant CD8(+) T cell recognition of SARS-CoV-2 epitopes in patients with COVID-19, coupled with strong activation features in these T cells. Compared to healthy individuals, patients with severe disease displayed larger populations of SARS-CoV-2-specific T cells.