A commensally regulated immune rheostat fine-tunes skin barrier fitness

At the skin’s surface, the epidermis must balance stem cell renewal with barrier maintenance to withstand environmental stress and shield against pathogens. In this study, we identify a microbial-immune-epithelial feedback mechanism that integrates environmental information into stem cell regulation in mice. Specifically, we show that Langerhans cells (LCs), an intraepithelial macrophage population, orchestrate this circuit by producing prostaglandin E ₂ , which restrains stem cell proliferation, promotes epidermal differentiation, and maintains barrier integrity during homeostasis. Upon pathway disruption, stem cells become overactivated, hindering terminal differentiation and weakening barrier function. Upstream, LC activity is tuned by the local microbial environment in a rheostat-like fashion, coupling commensal sensing to stem cell dynamics. Our findings provide a general framework for how barrier tissues achieve adaptive homeostasis amid continual external fluctuations.