title: Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells.
abstract: RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, ROR-γt-dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.
authors.affiliation: MRC Centre for Immune Regulation, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Withers
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Gastroenterology Division, Weill Cornell Medicine, New York, New York, USA.|Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA.|The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hepworth
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Gastroenterology Division, Weill Cornell Medicine, New York, New York, USA.|Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA.|The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Wang
authors.affiliation: MRC Centre for Immune Regulation, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Mackley
authors.affiliation: MRC Centre for Immune Regulation, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Halford
authors.affiliation: MRC Centre for Immune Regulation, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Dutton
authors.affiliation: MRC Centre for Immune Regulation, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Marriott
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Verena
authors.initials: V
authors.lastname: Brucklacher-Waldert
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Marc
authors.identifier: http://orcid.org/0000-0002-1478-9562
authors.initials: M
authors.lastname: Veldhoen
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Kelsen
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Baldassano
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Gastroenterology Division, Weill Cornell Medicine, New York, New York, USA.|Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA.|The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Sonnenberg
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology; D004756:Enterobacteriaceae Infections / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D057132:Nuclear Receptor Subfamily 1, Group F, Member 3