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.