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

Abstract

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.