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Microbial Regulation of CD141 Human Intestinal DCs Support ILC Production of IL‐22 in IBD: P‐241 YI

BACKGROUND: Interleukin (IL)-22 is an IL-10 family member that acts on epithelial cells to promote healing. Although initially characterized as a cytokine made by T cells (predominantly Th17 cells), more recent data has revealed the contribution of non-T cells, including lymphoid tissue inducer cells and innate lymphoid cells (ILCs), in IL-22 production. This emerging subset of ILCs plays an important role in mouse models of colitis, but their role in human IBD and regulation by intestinal microbiota remain less clear. METHODS: Lamina propria mononuclear cells (LPMCs) were isolated from both endoscopic biopsies and surgically resected intestinal tissue. Cytokine production was analyzed by flow cytometry. Dendritic cells (DCs) and ILCs were sorted by FACS. Dextran sodium sulfate (DSS) and Citrobacter rodentium were used to evaluate ILC function in chemical and infectious mouse models of colitis, respectively. RESULTS: By analysis of Th17 cytokine production in lamina propria mononuclear cells (LPMCs) from IBD patients and non-IBD controls, we show an increased production of IL22 in intestinal ILCs. Interestingly, IL22 production correlates with exposure to the fecal stream in patients with surgical diversion. Mouse models of both chemical and infectious colitis revealed the sufficiency for human microbiota to induce ILC production of IL-22 and the importance of MyD88 signaling in CD11c-expressing cells to promote protection by inducing IL-22 production by ILCs. Surprisingly, TLR-induced signaling in CD14þ, but not CD103þ, intestinal DCs support ILC production of IL22 via IL23 and IL1b. CONCLUSION(S): These results characterize an important class of ILCs producing IL-22 in mild to moderate IBD and suggest the importance of CD14þ intestinal DCs in integrating the microbial signals that regulate ILC function. The production and regulation of IL-22 by intestinal ILCs may have important implications for diagnostic and therapeutic developments in the clinical management of IBD.