title: Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease.
abstract: Type 1 interferon (IFN-1) promotes regulatory T-cell function to suppress inflammation in the mouse intestine, but little is known about IFN-1 in the human gut. We therefore assessed the influence of IFN-1 on CD4+ T-cells isolated from human colon tissue obtained from healthy controls or patients with inflammatory bowel disease (IBD). Immunofluorescent imaging revealed constitutive expression of IFNβ in human intestinal tissue, and colonic T-cells were responsive to exogenous IFN-1 as assessed by phosphorylation of signal transduction and activator of transcription 1 (pSTAT1) and induction of interferon stimulated genes (ISGs). Unlike their blood counterparts, intestinal T-cells from non-inflamed regions of IBD colon displayed enhanced responsiveness to IFN-1, increased frequency of pSTAT1+ cells, and greater induction of ISGs upon IFN-1 exposure in vitro. In healthy tissue, antibody neutralization of IFNβ selectively reduced T-cell production of the pro-regulatory cytokine interleukin-10 (IL-10) and increased IFNγ synthesis. In contrast, neutralization of IFNβ in IBD tissue cultures increased the frequency of T-cells producing inflammatory cytokines but did not alter IL-10 expression. These data support a role for endogenous IFN-1 as a context-dependent modulator of T-cell function that promotes regulatory activity in healthy human intestine, but indicate that the IFN-1/STAT1 pathway is dysregulated in inflammatory bowel disease.
authors.affiliation: Department of Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.|Department of Paediatric Gastroenterology, Monash Children's Hospital, Melbourne, VIC, Australia.
authors.forename: E M
authors.initials: EM
authors.lastname: Giles
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: T J
authors.initials: TJ
authors.lastname: Sanders
authors.affiliation: Department of Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
authors.forename: N E
authors.initials: NE
authors.lastname: McCarthy
authors.affiliation: Department of Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Lung
authors.affiliation: Department of Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Pathak
authors.affiliation: Department of Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
authors.forename: T T
authors.initials: TT
authors.lastname: MacDonald
authors.affiliation: Department of Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
authors.forename: J O
authors.initials: JO
authors.lastname: Lindsay
authors.affiliation: Department of Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Stagg
mesh_terms: D000293:Adolescent; D000818:Animals; D019138:Antibodies, Blocking / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D003106:Colon / Q000276:immunology*; D005260:Female; D006801:Humans; D056747:Immunomodulation; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D050794:STAT1 Transcription Factor; D016753:Interleukin-10; D016899:Interferon-beta; D007371:Interferon-gamma