Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3⁺ Treg cell function in the intestine.
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.
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
O J
OJ
Harrison
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
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N
Srinivasan
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
J
J
Pott
Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK.
C
C
Schiering
Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK.
T
T
Krausgruber
Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, UK.
N E
NE
Ilott
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
K J
KJ
Maloy
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D003092:Colitis / Q000276:immunology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000276:immunology; D018928:Immunity, Mucosal / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology*; D007422:Intestines / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020382:Interleukin-18