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, Joshua M.; Leistritz-Edwards, Del; Dunn, Augustine; Tarr, Christina; Lehman, Jesse; Dempsey, Conor; Hamel, Andrew; Rayon, Violeta; Liu, Gang; Wang, Yuntong; Wille, Marcos; Durkin, Melissa; Hadley, Kane; Sheena, Aswathy; Roscoe, Benjamin; Ng, Mark; Rockwell, Graham; Manto, Margaret; Gienger, Elizabeth; Nickerson, Joshua; Moarefi, Amir; Noble, Michael; Malia, Thomas; Bardwell, Philip D.; Gordon, William; Swain, Joanna; Skoberne, Mojca; Sauer, Karsten; Harris, Tim; Goldrath, Ananda W.; Shalek, Alex K.; Coyle, Anthony J.; Benoist, Christophe; Pregibon, Daniel C.

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 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 influence pre-existing immunity to SARS-CoV-2 and shape the immune repertoire upon subsequent viral exposure. One-Sentence Summary We perform a unified, multi-omic characterization of the CD8+ T cell response to SARS-CoV-2, revealing pre-existing immunity conditioned by HLA genotype.