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

Francis et al.▾ Francis, J.M., Leistritz-Edwards, D., Dunn, A., Tarr, C., Lehman, J., Dempsey, C., Hamel, A., Rayon, V., Liu, G., Wang, Y., Wille, M., Durkin, M., Hadley, K., Sheena, A., Roscoe, B., Ng, M., Rockwell, G., Manto, M., Gienger, E., Nickerson, J., MGH COVID-19 Collection and Processing Team, Moarefi, A., Noble, M., Malia, T., Bardwell, P.D., Gordon, W., Swain, J., Skoberne, M., Sauer, K., Harris, T., Goldrath, A.W., Shalek, A.K., Coyle, A.J., Benoist, C., Pregibon, D.C.

Science Immunology , Volume 7

November, 2021

Abstract

Effective presentation of antigens by 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, multi-omic technology to generate a unified ex vivo characterization of the CD8⁺ T cell response to SARS-CoV-2 across 4 major HLA class I alleles. We found that HLA genotype conditions key features of epitope specificity, TCR α/β 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 significantly influence the CD8⁺ T cell repertoire shape and utilization of immune recall upon SARS-CoV-2 infection.