Regulatory T Cells Promote Innate Inflammation after Skin Barrier Breach Via TGF-β Activation

Regulatory T cells (T regs ) use multiple mechanisms to attenuate inflammation and prevent autoimmunity. T regs residing in peripheral (i.e., nonlymphoid) tissues have specialized functions; specifically, skin T regs promote wound healing, suppress dermal fibrosis, facilitate epidermal regeneration, and augment hair follicle cycling. Here, we demonstrated that skin T regs 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 regs 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 regs . Upon skin injury, T regs 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 Staphylococcus aureus infection across a compromised barrier. Thus, αvβ8-expressing T regs in the skin, somewhat paradoxical to their canonical immunosuppressive functions, facilitated inflammation acutely after loss of barrier integrity to promote host defense against infection.