Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93

The interleukin (IL)-17 family, consisting of six members, promotes host defense but can in some context promote the development of autoimmune disease. Here, we examined the role of IL-17D, a poorly understood member in the IL-17 family. IL-17D was expressed primarily by colonic epithelial cells. Il17d−/− mice were more susceptible to acute colitis, bacterial infection and experimentally induced colon cancer than their wildtype counterparts. Il17d deficiency impaired IL-22 production by group 3 innate lymphoid cells (ILC3s) and reduced expression of IL-22-dependent antimicrobial peptides, RegIIIβ and RegIIIγ, in colon tissue at steady state and in colitis; this was associated with changes in microbial composition and dysbiosis. Protein purification studies revealed that IL-17D bound not canonical IL-17 receptors, but rather CD93, a glycoprotein expressed on mature ILC3s. Mice lacking Cd93 in ILC3s exhibited impaired IL-22 production and aggravated colonic inflammation in experimental colitis. Thus, an IL-17D-CD93 axis regulates ILC3 function to preserve intestinal homeostasis. [Display omitted] •IL-17D is required for intestinal hemostasis•IL-17D deficiency results in defective IL-22 production by ILC3s•CD93 is a functional receptor of IL-17D expressed on mature ILC3s•CD93 deficiency decreases ILC3 development and IL-22 production in ILC3s Among IL-17 cytokines, IL-17D is the least studied member. In this study, Dong et al. demonstrate that intestine epithelial cells-derived IL-17D serve as a critical factor in regulating ILC3s function and intestinal homeostasis by binding the receptor CD93.