Allelic variation in Class I HLA determines pre-existing memory responses to SARS-CoV-2 that shape the CD8+ T cell repertoire upon viral exposure
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.; Sheen, 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.
Show 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 the first 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 /{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 influence pre-existing immunity to SARS-CoV-2 and shape the immune repertoire upon subsequent viral exposure. One-Sentence SummaryWe perform a unified, multi-omic characterization of the CD8+ T cell response to SARS-CoV-2, revealing pre-existing immunity conditioned by HLA genotype.
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