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.

doi:10.1101/2021.04.29.441258

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bioRxiv · 10.1101/2021.04.29.441258

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

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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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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.. 2021-04-29. 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. https://doi.org/10.1101/2021.04.29.441258

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