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

Tissue-resident memory T cells (TRM) are non-recirculating cells that exist throughout the body. While TRM 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 chart TRM heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM function, durability and malleability. We find that unequal responsiveness to TGF-β is a major driver of this diversity. Strikingly, dampened TGF-b signaling engendered CD103- TRM with increased proliferative potential, enhanced function, and reduced longevity compared to their TGF-β-responsive CD103+ TRM counterparts. Further, while CD103- TRM readily modified their phenotype upon relocation, CD103+ TRM were comparatively resistant to trans-differentiation. Thus, despite common requirements for TRM development, adaptation of these cells to their tissue of residence confers discrete functional properties such that TRM exist along a spectrum of differentiation potential that is governed by their local microenvironment. Effector CD8+ OT-I Tcells or OT-I cells deficient in the TGFbRII were injected into HSV-OVA infected mice 2 days post-infection and sorted at day 14 post-infection from the epidermal skin. Cells were subject to RNA sequencing for transcriptional analysis.