Heterogeneous maintenance of human tissue resident memory T cells based on efflux capacities

Tissue-resident memory T cells (TRM) accelerate pathogen clearance through rapid and enhanced functional responses in situ. In humans, TRM cells are prevalent in diverse anatomic sites throughout the human lifespan, yet mechanisms for long-term maintenance are unknown. Here, we identify subpopulations of human TRM in mucosal and lymphoid sites based on differential efflux of mitochondrial dyes, with distinct transcriptional profiles, turnover, and functional capacities. TRM are enriched in efflux(+) populations compared with circulating memory CD8+T cells. Compared to efflux- TRM, efflux(+) TRM showed transcriptional and phenotypic features of quiescence including reduced turnover, decreased expression of exhaustion markers, and increased proliferative capacity and signaling to homeostatic cytokines. Moreover, efflux(+) and efflux(-) TRM subsets both maintain TRM characteristics when activated, while efflux(+) TRM produce IL-17 and efflux(-) produce higher levels of IFN-γ and IL-2. Our results suggest a model for cooperative maintenance of T cell immunity in tissues through interplay of subsets with complementary capacities for longevity and effector function.