Human intestinal tissue-resident memory CD8+ T cells comprise transcriptionally and functionally distinct subsets

FitzPatrick, M. E. B.; Provine, N. M.; Garner, L. C.; Powell, K.; Amini, A.; Irwin, S.; Ferry, H.; Ambrose, T.; Friend, P.; Vrakas, G.; Reddy, S.; Soilleux, E. J.; Klenerman, P.; Allan, P. J.

doi:10.1101/869917

bioRxiv · 10.1101/869917

Human intestinal tissue-resident memory CD8+ T cells comprise transcriptionally and functionally distinct subsets

FitzPatrick, M. E. B.·Provine, N. M.·Garner, L. C.·Powell, K.·Amini, A.·Irwin, S.·Ferry, H.·Ambrose, T.·Friend, P.·Vrakas, G.·Reddy, S.·Soilleux, E. J.·Klenerman, P.·Allan, P. J.

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Abstract

Tissue-resident memory T (TRM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However transcriptional heterogeneity of human intestinal TRM cells remains undefined, and definitive markers of CD103-TRM cells are lacking. Here, we investigated transcriptional and functional heterogeneity of human TRM cells through the study of donor-derived intestinal TRM cells from intestinal transplant recipients. Single-cell transcriptional profiling identified four conventional TRM populations, with two distinct transcriptional states of CD8+ TRM cells, delineated by ITGAE and ITGB2 expression. We defined a transcriptional signature discriminating the two CD8+ populations, including differential expression of key residency-associated genes and cytotoxic molecules. Flow cytometry of recipient-derived cells infiltrating the graft and intestinal lymphocytes from healthy gut confirmed the two CD8+ TRM phenotypes, with {beta}2-integrin acting as a CD103-CD8+ TRM marker. CD103+ CD8+ TRM cells produced IL-2, and demonstrated greater polyfunctional cytokine production, while {beta}2-integrin+ CD69+ CD103-TRM cells had higher granzyme expression. Phenotypic and functional analysis of intestinal CD4+ T cells identified many parallels, including a distinct {beta}2-integrin+ population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal TRM cells, and suggest a role for {beta}2-integrin in TRM development. SummaryHeterogeneity within human tissue-resident memory T (TRM) cells is poorly understood. We show that transcriptionally, phenotypically, and functionally distinct CD4+ and CD8+ TRM subsets exist in the human intestine, and that {beta}2-integrin expression identifies a distinct population of CD8+ TRM cells.

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FitzPatrick, M. E. B., Provine, N. M., Garner, L. C., Powell, K., Amini, A., Irwin, S., Ferry, H., Ambrose, T., Friend, P., Vrakas, G., Reddy, S., Soilleux, E. J., Klenerman, P., Allan, P. J.. 2019-12-11. Human intestinal tissue-resident memory CD8+ T cells comprise transcriptionally and functionally distinct subsets. https://doi.org/10.1101/869917

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