Regulatory T cells promote innate inflammation after skin barrier breach via TGF-β activation.

Regulatory T cells (T) use multiple mechanisms to attenuate inflammation and prevent autoimmunity. T residing in peripheral (i.e., nonlymphoid) tissues have specialized functions; specifically, skin T promote wound healing, suppress dermal fibrosis, facilitate epidermal regeneration, and augment hair follicle cycling. Here, we demonstrated that skin T were transcriptionally attuned to interact with their tissue environment through increased expression of integrin and TGF-β pathway genes that influence epithelial cell biology. We identified a molecular pathway where skin T license keratinocytes to promote innate inflammation after skin barrier breach. Using a single-cell discovery approach, we identified preferential expression of the integrin αvβ8 on skin T Upon skin injury, T used this integrin to activate latent TGF-β, which acted directly on epithelial cells to promote CXCL5 production and neutrophil recruitment. Induction of this circuit delayed epidermal regeneration but provided protection from infection across a compromised barrier. Thus, αvβ8-expressing T in the skin, somewhat paradoxical to their canonical immunosuppressive functions, facilitated inflammation acutely after loss of barrier integrity to promote host defense against infection.