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

Nat Commun. 2016 May 19:7:11627. doi: 10.1038/ncomms11627.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / physiology*
  • Colitis / immunology*
  • Disease Models, Animal
  • Female
  • Interleukin-17 / metabolism
  • Interleukin-22
  • Interleukin-23 / metabolism*
  • Interleukins / metabolism
  • Intestines / immunology*
  • Male
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Receptors, Interleukin / metabolism
  • T-Box Domain Proteins / metabolism*

Substances

  • Interleukin-17
  • Interleukin-23
  • Interleukins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Interleukin
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • interleukin-23 receptor, mouse