title: The alarmin IL-33 promotes regulatory T-cell function in the intestine.
abstract: FOXP3(+) regulatory T cells (Treg cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function; however, key host factors controlling the Treg response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites, where it functions as an endogenous danger signal, or alarmin, in response to tissue damage. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients, suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis, but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic Treg cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates Treg responses in several ways. First, it enhances transforming growth factor (TGF)-β1-mediated differentiation of Treg cells and, second, it provides a necessary signal for Treg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Schiering
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krausgruber
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Chomka
authors.affiliation: Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, and German Rheumatism Research Center (DRFZ), Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Fröhlich
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Krista
authors.initials: K
authors.lastname: Adelmann
authors.affiliation: Program in Barrier Immunity and Repair, Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Wohlfert
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, United Kingdom.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pott
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Thibault
authors.initials: T
authors.lastname: Griseri
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Bollrath
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Hegazy
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, United Kingdom.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Harrison
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Benjamin M J
authors.initials: BMJ
authors.lastname: Owens
authors.affiliation: Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, and German Rheumatism Research Center (DRFZ), Berlin, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Löhning
authors.affiliation: Program in Barrier Immunity and Repair, Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Belkaid
authors.affiliation: Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin, Ireland.
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
authors.affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Powrie
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018928:Immunity, Mucosal; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053759:Interleukin-23 / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D007422:Intestines / Q000166:cytology* / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018123:Receptors, Interleukin / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C506535:Il33 protein, mouse; D053759:Interleukin-23; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin; D016212:Transforming Growth Factor beta