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T-bet is a key modulator of IL-23-driven pathogenic CD4+ T cell responses in the intestine

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  • Thomas Krausgruber

    (Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
    The Kennedy Institute of Rheumatology, University of Oxford
    Present address: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, Austria)

  • Chris Schiering

    (Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
    Present address: The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, UK)

  • Krista Adelmann

    (Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital)

  • Oliver J. Harrison

    (Sir William Dunn School of Pathology, University of Oxford
    Present address: 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 20892-0485, USA)

  • Agnieszka Chomka

    (Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
    The Kennedy Institute of Rheumatology, University of Oxford)

  • Claire Pearson

    (Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
    The Kennedy Institute of Rheumatology, University of Oxford)

  • Philip P. Ahern

    (Sir William Dunn School of Pathology, University of Oxford
    Present address: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA)

  • Matthew Shale

    (Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
    Present address: Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California 94305, USA.)

  • Mohamed Oukka

    (Center for Immunity and Immunotherapies, Seattle Children’s Research Institute)

  • Fiona Powrie

    (Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
    The Kennedy Institute of Rheumatology, University of Oxford)

Abstract

IL-23 is a key driver of pathogenic Th17 cell responses. It has been suggested that the transcription factor T-bet is required to facilitate IL-23-driven pathogenic effector functions; however, the precise role of T-bet in intestinal T cell responses remains elusive. Here, we show that T-bet expression by T cells is not required for the induction of colitis or the differentiation of pathogenic Th17 cells but modifies qualitative features of the IL-23-driven colitogenic response by negatively regulating IL-23R expression. Consequently, absence of T-bet leads to unrestrained Th17 cell differentiation and activation characterized by high amounts of IL-17A and IL-22. The combined increase in IL-17A/IL-22 results in enhanced epithelial cell activation and inhibition of either IL-17A or IL-22 leads to disease amelioration. Our study identifies T-bet as a key modulator of IL-23-driven colitogenic responses in the intestine and has important implications for understanding of heterogeneity among inflammatory bowel disease patients.

Suggested Citation

  • Thomas Krausgruber & Chris Schiering & Krista Adelmann & Oliver J. Harrison & Agnieszka Chomka & Claire Pearson & Philip P. Ahern & Matthew Shale & Mohamed Oukka & Fiona Powrie, 2016. "T-bet is a key modulator of IL-23-driven pathogenic CD4+ T cell responses in the intestine," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11627
    DOI: 10.1038/ncomms11627
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    Cited by:

    1. Agnieszka K. Czopik & Eóin N. McNamee & Victoria Vaughn & Xiangsheng Huang & In Hyuk Bang & Trent Clark & Yanyu Wang & Wei Ruan & Tom Nguyen & Joanne C. Masterson & Eunyoung Tak & Sandra Frank & Colm , 2024. "HIF-2α-dependent induction of miR-29a restrains TH1 activity during T cell dependent colitis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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