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.