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 RM persistence requires autocrine TGFβ transactivated by integrins expressed on keratinocytes. T RM precursors that encounter antigen in the epidermis during development outcompete bystander T RM for TGFβ resulting in enhanced persistence. ScRNA-seq analysis of epidermal T RM revealed that local antigen experience in the skin resulted in an enhanced differentiation signature in comparison with bystanders. Upon recall, T RM displayed greater proliferation dictated by affinity of antigen experienced during epidermal development. Finally, local antigen experienced T RM differentially expressed TGFβRIII, which increases avidity of the TGFβRI/II receptor complex for TGFβ. Selective ablation of Tgfbr3 reduced local antigen experienced T RM capacity to persist, rendering them phenotypically like bystander T RM . Thus, antigen-driven TCR signaling in the epidermis during T RM differentiation results in a lower TGFβ requirement for persistence and increased proliferative capacity that together enhance epidermal T RM fitness.