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 Tregs 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-beta pathway genes that influence epithelial cell biology. We identified a molecular pathway where skin Tregs license keratinocytes to promote innate inflammation after skin barrier breach. Using a single-cell discovery approach, we identified preferential expression of the integrin alpha v beta 8 on skin T-regs. Upon skin injury, T-regs used this integrin to activate latent TGF-beta, 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, alpha v beta 8-expressing Tregs in the skin, somewhat paradoxical to their canonical immunosuppressive functions, facilitated inflammation acutely after loss of barrier integrity to promote host defense against infection.

Automated summary

Skin T-regs play a crucial role in regulating inflammation and protecting skin immunity, influencing epithelial cell biology through integrin and TGF-beta pathways. After skin injury, they activate TGF-beta and promote inflammation responses to protect the host from infection.