The Chemokine Receptor CXCR6 Controls the Functional Topography of Interleukin-22 Producing Intestinal Innate Lymphoid Cells

•CXCL16 and IL-23 are coexpressed by CD11b+CD103− intestinal DCs•Cxcr6 ablation leads to a selective loss of NKp46+ ILC3s from the intestine•Cxcr6 is required for homeostasis of RORγt+ ILC3s in the intestinal villus•Cxcr6 deficiency results in loss of IL-22-mediated protection against C. rodentium

SummaryInterleukin-22 (IL-22) plays a critical role in mucosal defense, although the molecular mechanisms that ensure IL-22 tissue distribution remain poorly understood. We show that the CXCL16-CXCR6 chemokine-chemokine receptor axis regulated group 3 innate lymphoid cell (ILC3) diversity and function. CXCL16 was constitutively expressed by CX3CR1+ intestinal dendritic cells (DCs) and coexpressed with IL-23 after Citrobacter rodentium infection. Intestinal ILC3s expressed CXCR6 and its ablation generated a selective loss of the NKp46+ ILC3 subset, a depletion of intestinal IL-22, and the inability to control C. rodentium infection. CD4+ ILC3s were unaffected by CXCR6 deficiency and remained clustered within lymphoid follicles. In contrast, the lamina propria of Cxcr6−/− mice was devoid of ILC3s. The loss of ILC3-dependent IL-22 epithelial stimulation reduced antimicrobial peptide expression that explained the sensitivity of Cxcr6−/− mice to C. rodentium. Our results delineate a critical CXCL16-CXCR6 crosstalk that coordinates the intestinal topography of IL-22 secretion required for mucosal defense.

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