title: Skin-derived TSLP systemically expands regulatory T cells.
abstract: Regulatory T cells (Tregs) are a subset of CD4+T cells with suppressive function and are critical for limiting inappropriate activation of T cells. Hence, the expansion of Tregs is an attractive strategy for the treatment of autoimmune diseases. Here, we demonstrate that the skin possesses the remarkable capacity to systemically expand Treg numbers by producing thymic stromal lymphopoietin (TSLP) in response to vitamin D receptor stimulation. An ∼2-fold increase in the proportion and absolute number of Tregs was observed in mice treated topically but not systemically with the Vitamin D3 analog MC903. This expansion of Tregs was dependent on TSLP receptor signaling but not on VDR signaling in hematopoietic cells. However, TSLP receptor expression by Tregs was not required for their proliferation. Rather, skin-derived TSLP promoted Treg expansion through dendritic cells. Importantly, treatment of skin with MC903 significantly lowered the incidence of autoimmune diabetes in non-obese diabetic mice and attenuated disease score in experimental autoimmune encephalomyelitis. Together, these data demonstrate that the skin has the remarkable potential to control systemic immune responses and that Vitamin D-mediated stimulation of skin could serve as a novel strategy to therapeutically modulate the systemic immune system for the treatment of autoimmunity.
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, United States.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Leichner
authors.affiliation: First Department of Internal Medicine, Kansai Medical University, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Satake
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, United States.
authors.forename: Victor Sanoe
authors.initials: VS
authors.lastname: Harrison
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, United States.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Neurology, Washington University School of Medicine, United States.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Archambault
authors.affiliation: Division of Dermatology, Department of Medicine, Department of Anesthesiology, Department of Pathology and Immunology, Center for the Study of Itch, United States.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Center for Immunity and Inflammation, Department of Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, United States.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Siracusa
authors.affiliation: National Institutes of Health, United States.
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.affiliation: Department of Surgery, University of Pennsylvania, United States.
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.affiliation: Department of Neurology, Washington University School of Medicine, United States.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Wu
authors.affiliation: Department of Medicine, Weill Cornell Medical College, United States.
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Pennsylvania, United States. Electronic address: taku.kambayashi@uphs.upenn.edu.
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
mesh_terms: D000818:Animals; D015415:Biomarkers; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D015415:Biomarkers; D016207:Cytokines; D002762:Cholecalciferol; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse
keywords: Immunotherapy; Regulatory T cells; Thymic stromal lymphopoietin; Tolerance; Vitamin D