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

Thomas Krausgruber (), Chris Schiering (), Krista Adelmann, Oliver J. Harrison, Agnieszka Chomka, Claire Pearson, Philip P. Ahern, Matthew Shale, Mohamed Oukka and Fiona Powrie ()
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Thomas Krausgruber: Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
Chris Schiering: Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
Krista Adelmann: Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
Oliver J. Harrison: Sir William Dunn School of Pathology, University of Oxford
Agnieszka Chomka: Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
Claire Pearson: Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
Philip P. Ahern: Sir William Dunn School of Pathology, University of Oxford
Matthew Shale: Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital
Mohamed Oukka: Center for Immunity and Immunotherapies, Seattle Children’s Research Institute
Fiona Powrie: Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11627

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