Epidermal resident memory T cell fitness requires antigen encounter in the skin.

CD8+ tissue-resident memory T cells (TRM) develop from effectors that seed peripheral tissues where they persist providing defense against subsequent challenges. TRM persistence requires autocrine TGFβ transactivated by integrins expressed on keratinocytes. TRM precursors that encounter antigen in the epidermis during development outcompete bystander TRM for TGFβ resulting in enhanced persistence. ScRNA-seq analysis of epidermal TRM revealed that local antigen experience in the skin resulted in an enhanced differentiation signature in comparison with bystanders. Upon recall, TRM displayed greater proliferation dictated by affinity of antigen experienced during epidermal development. Finally, local antigen experienced TRM differentially expressed TGFβRIII, which increases avidity of the TGFβRI/II receptor complex for TGFβ. Selective ablation of Tgfbr3 reduced local antigen experienced TRM capacity to persist, rendering them phenotypically like bystander TRM. Thus, antigen-driven TCR signaling in the epidermis during TRM differentiation results in a lower TGFβ requirement for persistence and increased proliferative capacity that together enhance epidermal TRM fitness.