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

Sunil Kumar Saini*, Ditte Stampe Hersby, Tripti Tamhane, Helle Rus Povlsen, Susana Patricia Amaya Hernandez, Morten Nielsen, Anne Ortved Gang, Sine Reker Hadrup

*Corresponding author for this work

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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 (MHC) class I-binding peptides covering the complete SARS-CoV-2 genome. Using DNA-barcoded peptide-MHC complex (pMHC) 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 COVID-19 patients, with up to 27% of all CD8+ lymphocytes interacting with SARS-CoV-2-derived epitopes. Most immunogenic regions were derived from open reading frame (ORF) 1 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 pre-existing T cell recognition signature was partially overlapping with the epitope landscape observed in COVID-19 patients and may drive the further expansion of T cell responses to SARS-CoV-2 infection. Importantly the phenotype of the SARS-CoV-2-specific CD8+ T cells, revealed a strong T cell activation in COVID-19 patients, while 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 to 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.

Original languageEnglish
Article numbereabf7550
JournalScience immunology
Issue number58
Number of pages22
Publication statusPublished - 2021

Bibliographical note

Funding Information:
The work is supported by the Independent Research Fund Denmark (grant no. 0214-00053B, 2020) to S.R.H.


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