Immunopathogenesis of IBD: Batf as a Key Driver of Disease Activity

Dig Dis. 2016:34 Suppl 1:40-7. doi: 10.1159/000447281. Epub 2016 Aug 22.


Background: Inflammatory bowel diseases (IBDs) represent a group of chronic immune-mediated disorders that are influenced by a genetic predisposition and additional environmental triggers. Genome-wide association studies strongly implicate that a number of immune system-related genetic variations are critically contributing to the initiation and promotion of intestinal inflammation. Especially the identification of the strong association of a series of single nucleotide polymorphisms including interleukin (IL)-23R, CCR6, signal transducer and activator of transcription 3 (Stat3) and Stat4 with IBD susceptibility point at a critical involvement of T cells and especially of IL-17a-producing Th17 cells in the immune pathogenesis of IBD. In line with this hypothesis, a series of preclinical studies have unequivocally established that T cells are key drivers of immune-mediated colitis. Interestingly, especially Th17 cells were identified to be highly prevalent in inflamed IBD tissues, a finding that seems to be functionally relevant as genetic inactivation studies in the mouse resulted in almost complete suppression of colitis development.

Key messages: While targeting Th17 cell differentiation regulating transcription factors, as retinoic acid-related orphan receptor gamma t (RORγt) is effective in preventing murine colitis, one concern of drugs targeting RORγt in a clinical setting represents the large body of murine data unambiguously demonstrating that additional pathways within and outside the immune system are equally RORγt-dependent increasing the risk of undesirable side effects. The AP1 transcription factor Batf (B cell-activating transcription factor) appears to exclusively regulate pathways within lymphocytes. Importantly, Batf represents a central regulator of Th17 cell development and is strongly upregulated within IBD-affected tissues. Employing 2 acute colitis models, we demonstrate in this study that Batf-expressing T cells are critical drivers of T cell-mediated colitis while in contrast to Stat3 loss of Batf does not affect intestinal epithelial cell homeostasis ex vivo.

Conclusions: Targeting Batf in IBD emerges as an attractive therapeutic approach disabling colitogenic T cell activities while sparing off-target effects in the intestinal epithelial cell compartment.

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / antagonists & inhibitors
  • Basic-Leucine Zipper Transcription Factors / physiology*
  • Cell Differentiation / genetics
  • Colitis / chemically induced
  • Colitis / genetics*
  • Colitis / metabolism
  • Epithelial Cells / metabolism
  • Humans
  • Inflammatory Bowel Diseases / chemically induced
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / metabolism
  • Interleukin-17 / metabolism
  • Intestinal Mucosa / metabolism
  • Intestines / pathology
  • Mice
  • Polymorphism, Single Nucleotide
  • Receptors, CCR6 / genetics
  • Receptors, Interleukin / genetics
  • Receptors, Retinoic Acid / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT4 Transcription Factor / genetics
  • Th17 Cells / physiology*


  • Basic-Leucine Zipper Transcription Factors
  • Batf protein, mouse
  • CCR6 protein, mouse
  • Interleukin-17
  • Receptors, CCR6
  • Receptors, Interleukin
  • Receptors, Retinoic Acid
  • STAT3 Transcription Factor
  • STAT4 Transcription Factor
  • interleukin-23 receptor, mouse
  • retinoic acid receptor gamma