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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.)

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.)