Allelic variation in class I HLA determines CD8+ T cell repertoire shape and cross-reactive memory responses to SARS-CoV-2

Effective presentation of antigens by human leukocyte antigen (HLA) class I molecules to CD8(+) T cells is required for viral elimination and generation of long-term immunological memory. In this study, we applied a single-cell, multiomic technology to generate a unified ex vivo characterization of the CD8(+) T cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across four major HLA class I alleles. We found that HLA genotype conditions key features of epitope specificity, TCR alpha/beta sequence diversity, and the utilization of pre-existing SARS-CoV-2-reactive memory T cell pools. Single-cell transcriptomics revealed functionally diverse T cell phenotypes of SARS-CoV-2-reactive T cells, associated with both disease stage and epitope specificity. Our results show that HLA variations notably influence the CD8(+) T cell repertoire shape and utilization of immune recall upon SARS-CoV-2 infection.

Automated summary

HLA genotype conditions the CD8(+) T cell response to SARS-CoV-2, influencing epitope specificity, TCR sequence diversity, and utilization of immune memory T cells. Single-cell transcriptomics revealed functional diversity of SARS-CoV-2-reactive T cells associated with disease stage and epitope specificity.