title: PTPN2 controls differentiation of CD4⁺ T cells and limits intestinal inflammation and intestinal dysbiosis.
abstract: Loss-of-function variants within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with increased risk for Crohn's disease (CD). A disturbed regulation of T helper (Th) cell responses causing loss of tolerance against self- or commensal-derived antigens and an altered intestinal microbiota plays a pivotal role in CD pathogenesis. Loss of PTPN2 in the T-cell compartment causes enhanced induction of Th1 and Th17 cells, but impaired induction of regulatory T cells (Tregs) in several mouse colitis models, namely acute and chronic dextran sodium sulfate colitis, and T-cell transfer colitis models. This results in increased susceptibility to intestinal inflammation and intestinal dysbiosis which is comparable with that observed in CD patients. We detected inflammatory infiltrates in liver, kidney, and skin and elevated autoantibody levels indicating systemic loss of tolerance in PTPN2-deficient animals. CD patients featuring a loss-of-function PTPN2 variant exhibit enhanced Th1 and Th17 cell, but reduced Treg markers when compared with PTPN2 wild-type patients in serum and intestinal tissue samples. Our data demonstrate that dysfunction of PTPN2 results in aberrant T-cell differentiation and intestinal dysbiosis similar to those observed in human CD. Our findings indicate a novel and crucial role for PTPN2 in chronic intestinal inflammation.
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: M R
authors.initials: MR
authors.lastname: Spalinger
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Institute of Food, Nutrition and Health, ETH-Zurich, Zurich, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Chassard
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Raselli
authors.affiliation: 1] Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland [2] Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Frey-Wagner
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Gottier
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Lang
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Atrott
authors.affiliation: 1] Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland [2] Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: S R
authors.initials: SR
authors.lastname: Vavricka
authors.affiliation: Institute of Experimental Immunology, Department of Neuroimmunology, University of Zurich, Zurich, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Mair
authors.affiliation: Institute of Experimental Immunology, Department of Neuroimmunology, University of Zurich, Zurich, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Becher
authors.affiliation: Institute of Food, Nutrition and Health, ETH-Zurich, Zurich, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Lacroix
authors.affiliation: 1] Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland [2] Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Fried
authors.affiliation: 1] Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland [2] Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Rogler
authors.affiliation: 1] Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland [2] Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Scharl
mesh_terms: D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D003092:Colitis / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D064806:Dysbiosis; D000069196:Gastrointestinal Microbiome; D015870:Gene Expression; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D050791:STAT Transcription Factors; D014157:Transcription Factors; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2