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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 (Tregs) reside in nonlymphoid tissues where they carry out unique functions. The molecular mechanisms responsible for Treg accumulation and maintenance in these tissues are relatively unknown. Using an unbiased discovery approach, we identified LAYN (layilin), a C-type lectin-like receptor, to be preferentially and highly expressed on a subset of activated Tregs in healthy and diseased human skin. Expression of layilin on Tregs was induced by TCR-mediated activation in the presence of IL-2 or TGF-β. Mice with a conditional deletion of layilin in Tregs had reduced accumulation of these cells in tumors. However, these animals somewhat paradoxically had enhanced immune regulation in the tumor microenvironment, resulting in increased tumor growth. Mechanistically, layilin expression on Tregs had a minimal effect on their activation and suppressive capacity in vitro. However, expression of this molecule resulted in a cumulative anchoring effect on Treg dynamic motility in vivo. Taken together, our results suggest a model whereby layilin facilitates Treg adhesion in skin and, in doing so, limits their suppressive capacity. These findings uncover a unique mechanism whereby reduced Treg motility acts to limit immune regulation in nonlymphoid organs and may help guide strategies to exploit this phenomenon for therapeutic benefit., (Copyright © 2021 by The American Association of Immunologists, Inc.)

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.)

Tumor-infiltrating CD8+ T cells mediate antitumor immune responses. However, the mechanisms by which T cells remain poised to kill cancer cells despite expressing high levels of inhibitory receptors are unknown. Here, we report that layilin, a C-type lectin domain-containing membrane glycoprotein, is selectively expressed on highly activated, clonally expanded, but phenotypically exhausted CD8+ T cells in human melanoma. Lineage-specific deletion of layilin on murine CD8+ T cells reduced their accumulation in tumors and increased tumor growth in vivo. Congruently, gene editing of LAYN in human CD8+ T cells reduced direct tumor cell killing ex vivo. On a molecular level, layilin colocalized with integrin αLβ2 (LFA-1) on T cells, and cross-linking layilin promoted the activated state of this integrin. Accordingly, LAYN deletion resulted in attenuated LFA-1-dependent cellular adhesion. Collectively, our results identify layilin as part of a molecular pathway in which exhausted or "dysfunctional" CD8+ T cells enhance cellular adhesiveness to maintain their cytotoxic potential., Competing Interests: Disclosures: K.M. Mahuron reported grants from TRex Bio, Inc. during the conduct of the study; in addition, K.M. Mahuron had a patent to compositions and methods involving layilin pending. J.M. Moreau reported grants from TRex Bio, Inc. during the conduct of the study; in addition, J.M. Moreau had a patent to compositions and methods involving layilin pending. M.L. Pauli reported grants from TRex Bio, Inc. during the conduct of the study; personal fees from TRex Bio, Inc. outside the submitted work; and has been a consultant for TRex Bio, Inc. since January 2019. R.M. Feldman reported personal fees from TRex Bio, Inc. during the conduct of the study and personal fees from TRex Bio, Inc. outside the submitted work. P. Mehta reported grants from TRex Bio, Inc. during the conduct of the study; in addition, P. Mehta had a patent to compositions and methods involving layilin pending. M.M. Lowe reported a patent to UCSF/TRex Bio, Inc. pending. A. Marson reported personal fees from Arsenal Biosciences, Spotlight Therapeutics, PACT Pharma, Trizell, Juno Therapeutics, Health Advances, Lonza, Bernstein, AbbVie, Genentech, Merck, Illumina, Arcus, Jackson Laboratories, Nanostring Technologies, GLG, and Rupert Case Management; grants from Juno Therapeutics, Epinomics, Sanofi, and Gilead; non-financial support from Illumina; grants from Parker Institute for Cancer Immunotherapy; personal fees from AlphaSights, ALDA, and Amgen; "other" from ThermoFisher outside the submitted work; and reporting an inventorship on IP licensed to Arsenal Biosciences, Juno Therapeutics, and Fate Therapeutics. J. Wells reported grants from TRex Bio, Inc. during the conduct of the study, grants from Celgene, and personal fees from Cytomix outside the submitted work. R. Jupp was an employee of TRex Bio, Inc. at the time of the study. A.I. Daud reported "other" from TRex Bio, Inc. during the conduct of the study; grants from Merck, BMS, Roche, and Novartis; "other" from Genentech; grants from Checkmate and Incyte; personal fees from Array; and grants from Xencor, Curis, and OncoSec outside the submitted work. M.D. Rosenblum reported grants from TRex Bio, Inc. during the conduct of the study; personal fees from TRex Bio, Inc. outside the submitted work; and had a patent to UCSF/TRex Bio, Inc. pending. No other disclosures were reported., (© 2020 Mahuron et al.)