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Inflammation early in life can prime the local immune milieu of peripheral tissues, which can cause lasting changes in immunological tone that confer disease protection or susceptibility 1 . The cellular and molecular mechanisms that prompt changes in immune tone in many nonlymphoid tissues remain largely unknown. Here we find that time-limited neonatal inflammation induced by a transient reduction in neonatal regulatory T cells causes a dysregulation of subcutaneous tissue in mouse skin. This is accompanied by the selective accumulation of type 2 helper T (T H 2) cells within a distinct microanatomical niche. T H 2 cells are maintained into adulthood through interactions with a fibroblast population in skin fascia that we refer to as T H 2-interacting fascial fibroblasts (TIFFs), which expand in response to T H 2 cytokines to form subcutaneous fibrous bands. Activation of the T H 2-TIFF niche due to neonatal inflammation primes the skin for altered reparative responses to wounding. Furthermore, we identify fibroblasts in healthy human skin that express the TIFF transcriptional signature and detect these cells at high levels in eosinophilic fasciitis, an orphan disease characterized by inflammation and fibrosis of the skin fascia. Taken together, these data define a previously unidentified T H 2 cell niche in skin and functionally characterize a disease-associated fibroblast population. The results also suggest a mechanism of immunological priming whereby inflammation early in life creates networks between adaptive immune cells and stromal cells to establish an immunological set-point in tissues that is maintained throughout life., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)