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

Tissue-resident memory T (T-RM) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However, transcriptional heterogeneity of human intestinal T-RM cells remains undefined. Here, we investigate transcriptional and functional heterogeneity of human T-RM cells through study of donor-derived T-RM cells from intestinal transplant recipients. Single-cell transcriptional profiling identifies two transcriptional states of CD8(+) T-RM cells, delineated by ITGAE and ITGB2 expression. We define a transcriptional signature discriminating these populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft, and lymphocytes from healthy gut, confirm these CD8(+) T-RM phenotypes. CD8(+)CD69(+)CD103(+) T-RM cells produce interleukin-2 ( IL-2) and demonstrate greater polyfunctional cytokine production, whereas beta 2-integrin(+)CD69(+)CD103(-) T-RM cells have higher granzyme expression. Analysis of intestinal CD4(+) T cells identifies several parallels, including a beta 2-integrin(+) population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4(+) and CD8(+) T-RM cells.

Automated summary

This study investigates the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4(+) and CD8(+) T-RM cells using donor-derived T-RM cells from intestinal transplant recipients. Single-cell transcriptional profiling identifies two transcriptional states of CD8(+) T-RM cells, delineated by ITGAE and ITGB2 expression. The results describe the differential expression of cytotoxicity- and residency-associated genes in these populations, highlighting the complexity of T-RM cell diversity in the human intestine.