Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3⁺ Treg cell function in the intestine

Mucosal Immunol. 2015 Nov;8(6):1226-36. doi: 10.1038/mi.2015.13. Epub 2015 Mar 4.


Elevated levels of interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD), and polymorphisms in the IL18R1-IL18RAP locus are associated with IBD susceptibility. IL-18 is an IL-1 family cytokine that has been proposed to promote barrier function in the intestine, but the effects of IL-18 on intestinal CD4(+) T cells are poorly understood. Here we demonstrate that IL-18R1 expression is enhanced on both effector and regulatory CD4(+) T cells in the intestinal lamina propria, with T helper type 17 (Th17) cells exhibiting particularly high levels. We further show that, during steady state, intestinal epithelial cells constitutively secrete IL-18 that acts directly on IL-18R1-expressing CD4(+) T cells to limit colonic Th17 cell differentiation, in part by antagonizing IL-1R1 signaling. In addition, although IL-18R1 is not required for colonic Foxp3(+) regulatory T (Treg) cell differentiation, we found that IL-18R1 signaling was critical for Foxp3(+) Treg cell-mediated control of intestinal inflammation, where it promoted the expression of key Treg effector molecules. Thus IL-18 is a key epithelial-derived cytokine that differentially regulates distinct subsets of intestinal CD4(+) T cells during both homeostatic and inflammatory conditions, a finding with potential implications for treatment of chronic inflammatory disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Differentiation / immunology
  • Cell Separation
  • Colitis / immunology*
  • Disease Models, Animal
  • Fluorescent Antibody Technique
  • Forkhead Transcription Factors / immunology
  • Immunity, Mucosal / immunology
  • Interleukin-18 / immunology*
  • Intestinal Mucosa / immunology*
  • Intestines / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / immunology*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-18