Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system

Cell. 2007 Oct 5;131(1):33-45. doi: 10.1016/j.cell.2007.08.017.

Abstract

Inflammatory bowel disease (IBD) has been attributed to overexuberant host immunity or the emergence of harmful intestinal flora. The transcription factor T-bet orchestrates inflammatory genetic programs in both adaptive and innate immunity. We describe a profound and unexpected function for T-bet in influencing the behavior of host inflammatory activity and commensal bacteria. T-bet deficiency in the innate immune system results in spontaneous and communicable ulcerative colitis in the absence of adaptive immunity and increased susceptibility to colitis in immunologically intact hosts. T-bet controls the response of the mucosal immune system to commensal bacteria by regulating TNF-alpha production in colonic dendritic cells, critical for colonic epithelial barrier maintenance. Loss of T-bet influences bacterial populations to become colitogenic, and this colitis is communicable to genetically intact hosts. These findings reveal a novel function for T-bet as a peacekeeper of host-commensal relationships and provide new perspectives on the pathophysiology of IBD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Colitis, Ulcerative* / immunology
  • Colitis, Ulcerative* / microbiology
  • Colitis, Ulcerative* / pathology
  • Colitis, Ulcerative* / physiopathology
  • Colon / cytology
  • Colon / metabolism
  • Colon / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology
  • Female
  • Gene Expression Regulation
  • Humans
  • Immunity, Innate*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Intestinal Mucosa* / immunology
  • Intestinal Mucosa* / microbiology
  • Intestinal Mucosa* / pathology
  • Mice
  • Mice, Knockout
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • DNA-Binding Proteins
  • Interleukin-2 Receptor alpha Subunit
  • Rag2 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Tumor Necrosis Factor-alpha