Epithelial-Derived IL-18 Regulates Th17 Cell Differentiation and Foxp3(+) Treg Cell Function in the Intestine

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Harrison OJ, Srinivasan N, Pott J, Schiering C, Krausgruber T, Ilott NE, Maloy

Intestinal immune homeostasis is maintained through a constant molecular dialogue between commensal microbiota, intestinal tissue cells, and the mucosal immune system. Breakdown of this mutualistic relationship results in chronic pathologies of the gastrointestinal tract, including inflammatory bowel disease (IBD). 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, key regulators of intestinal homeostasis, are poorly understood. We demonstrated that IL-18R1 expression is enhanced on both effector and regulatory CD4+ T cells in the intestinal lamina propria, with Th17 cells exhibiting particularly high levels. We further demonstrated 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 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 deferentially 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.

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