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

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 TGFβ is a major driver of this diversity. Notably, dampened TGFβ signaling results in CD103^- T_RM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFβ-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.