Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity

Tissue-resident memory T (T-RM) cells are distributed throughout the body as relatively sessile populations. Mackay and colleagues find that the tissue in which T-RM cells are generated dictates their properties and is in turn defined according to T-RM-cell-intrinsic sensitivity to signaling via the cytokine TGF beta. Tissue-resident memory T (T-RM) cells are non-recirculating cells that exist throughout the body. Although T-RM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze T-RM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate T-RM cell function, durability and malleability. We find that unequal responsiveness to TGF beta is a major driver of this diversity. Notably, dampened TGF beta signaling results in CD103(-) T-RM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGF beta-responsive CD103(+) T-RM counterparts. Furthermore, whereas CD103(-) T-RM cells readily modified their phenotype upon relocation, CD103(+) T-RM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for T-RM cell development, tissue adaptation of these cells confers discrete functional properties such that T-RM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.