A commensally regulated immune rheostat fine-tunes skin barrier fitness

At the skins surface, the epidermis must balance stem cell renewal with barrier maintenance to withstand environmental stress and shield against pathogens. Here, we identify a microbial-immune-epithelial feedback mechanism that integrates environmental information into stem cell regulation. Specifically, we show that Langerhans cells--an intra-epithelial macrophage population-- orchestrate this circuit by producing prostaglandin E2, which restrains stem cell proliferation, promotes epidermal differentiation and maintains barrier integrity during homeostasis. Upon pathway disruption, stem cells become overactivated, impairing differentiation and compromising barrier function. Upstream, Langerhans cell activity is tuned by the local microbial environment in a rheostat-like fashion, coupling commensal sensing to stem cell control. Our findings provide a general framework for how barrier tissues achieve adaptive homeostasis amid continual external challenge.