Epidermal Resident Memory T Cell Fitness Requires Antigen Encounter in the Skin

CD8⁺tissue resident memory T cells (T_RM) develop from effectors that seed peripheral tissues where they persist providing defense against subsequent challenges. T_RMpersistence requires autocrine TGFβ transactivated by integrins expressed on keratinocytes. T_RMprecursors that encounter antigen in the epidermis during development outcompete bystander T_RMfor TGFβ resulting in enhanced persistence. ScRNA-seq analysis of epidermal T_RMrevealed that local antigen experience in the skin resulted in an enhanced differentiation signature in comparison with bystanders. Upon recall, T_RMdisplayed greater proliferation dictated by affinity of antigen experienced during epidermal development. Finally, local antigen experienced T_RMdifferentially expressed TGFβRIII, which increases avidity of the TGFβRI/II receptor complex for TGFβ. Selective ablation ofTgfbr3reduced local antigen experienced T_RMcapacity to persist, rendering them phenotypically like bystander T_RM. Thus, antigen driven TCR signaling in the epidermis during T_RMdifferentiation results in a lower TGFβ requirement for persistence and increased proliferative capacity that together enhance epidermal T_RMfitness.