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

Mucosal Immunology
Oliver J HarrisonK J Maloy

Abstract

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...Continue Reading

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Datasets Mentioned

BETA
E-MTAB-3067

Methods Mentioned

BETA
biopsies
IEC
flow cytometry
FACS
electrophoresis

Software Mentioned

Limma
FlowJo
GenomeStudio
R
ArrayExpress
Olympus Fluoview
Lumi
Bioconductor

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