Interleukin-10 production by innate lymphoid cells promotes intestinal immune homeostasis in mice

Abstract

Interleukin-10 (IL-10) is an immunomodulatory cytokine critical for intestinal immune homeostasis. IL-10 is produced by various immune cells but IL-10 receptor signaling in intestinal CX3CR1+ mononuclear phagocytes is necessary to prevent spontaneous colitis in mice. Here, we utilized fluorescent protein reporters and cell-specific targeting and found that Rorc-expressing innate lymphoid cells (ILCs) produce IL-10 in response to anti-CD40-mediated intestinal inflammation. Deletion of Il10 specifically in Rorc-expressing ILCs led to phenotypic changes in intestinal macrophages and exacerbated both innate and adaptive immune-mediated models of experimental colitis. The population of IL-10+ producing ILCs shared markers with both ILC2 and ILC3 with nearly all ILC3s being of the NCR+ subtype. Interestingly, Ccl26 was enriched in IL-10+ ILCs and was markedly reduced in IL-10-deficient ILC3s. Since CCL26 is a ligand for CX3CR1, we employed RNA in situ hybridization and observed increased numbers of ILCs in close proximity to Cx3cr1-expressing cells under inflammatory conditions. Finally, we generated transgenic RorctdTomato reporter mice that faithfully marked RORγt+ cells that could rescue disease pathology and aberrant macrophage phenotype following adoptive transfer into mice with selective Il10 deficiency in ILC3s. These results demonstrate that IL-10 production by a population of ILCs functions to promote immune homeostasis in the intestine possibly via direct effects on intestinal macrophages.