Interleukin-10 Receptor Signaling in Innate Immune Cells Regulates Mucosal Immune Tolerance and Anti-Inflammatory Macrophage Function

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4+ T cell transfer, Rag2−/−Il10rb−/− mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb−/− anti-inflammatory macrophages ameliorated colitis induction by WT CD4+ T cells in Rag2−/−Il10rb−/− mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans. [Display omitted] •IL-10R-deficient innate immune cells render WT CD4+ T cells colitogenic•Loss of innate IL-10R signaling impairs regulatory T cell generation and function•IL-10R signaling regulates murine and human macrophage differentiation and function