Development of Fit Epidermal Resident Memory T Cells Requires Antigen Encounter in the Skin.

CD8+ tissue resident memory T cells (TRM) develop from effectors that are recruited into peripheral tissues by infection or inflammation where they persist and provide defense against subsequent challenges. Long-term persistence of epidermal TRM requires autocrine TGFβ that is transactivated by integrins expressed on keratinocytes. In response to inflammation, the availability of TGFβ transactivation is limited. Antigen-experienced TRM that encountered antigen in the epidermis during their development are more fit and outcompete bystander TRM for TGFβ transactivation resulting in their enrichment in the epidermis. Transcriptomic analysis of endogenous epidermal TRM revealed that antigen-experienced TRM were enriched for TRM signature genes while bystander TRM retained the transcriptome of an earlier developmental state. Following antigen recall, antigen-experienced TRM displayed accelerated proliferation kinetics compared with bystanders that was determined by the TCR signal-strength during their differentiation the skin. Finally, antigen experienced TRM expressed TGFβRIII, which increases avidity of the TGFβRI/II receptor complex. Selective ablation of Tgfbr3 from antigen experienced TRM reduced their capacity to persist when TGFβ activation was limited thus rendering them phenotypically like bystander TRM. In sum, antigen-driven TCR signaling in the epidermis during TRM differentiation represents a required final step in ontogeny resulting in a lowered requirement on TGFβ transactivation for persistence and increased proliferation during recall responses that together result in the enhanced fitness of antigen-experience epidermal TRM.