Regulatory T cells promote innate inflammation after skin barrier breach via TGF-╬▓ activation
Tregs potentiate skin inflammation
Regulatory T cells (Tregs) regulate various immune responses all over the body, with their specific roles differing between anatomical locations. In the skin, Tregs help control wound healing, but the details of their role in this process are unclear. Here, Moreau et al. use transcriptomics and various conditional knockout mouse models to show that Tregs in the skin have heightened TGF-╬▓ signaling and ╬▒v╬▓8 integrin expression, which contributes to delayed epidermal repair after inducing skin injury. Specifically, ╬▒v╬▓8 expression in skin Tregs helps to activate TGF-╬▓ in neighboring keratinocytes, leading to innate immune influx and protection from Staphylococcus aureus infection. Together, these data provide a better understanding of the interactions between Tregs and epithelial cells in the skin during skin injury and bacterial infection.
Abstract
Regulatory T cells (Tregs) use multiple mechanisms to attenuate inflammation and prevent autoimmunity. Tregs 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 Tregs were transcriptionally attuned to interact with their tissue environment through increased expression of integrin and TGF-╬▓ 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 ╬▒v╬▓8 on skin Tregs. Upon skin injury, Tregs used this integrin to activate latent TGF-╬▓, 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, ╬▒v╬▓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.
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