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 Tcells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4+ Tcell 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+ Tcells 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.
Bibliographical noteFunding Information:
D.S.S is a recipient of a Research Fellowship Award Grant from the Crohn’s and Colitis Foundation of America (RFA 3784). S.B.S is supported by NIH Grants HL59561, DK034854, and AI50950, the Helmsley Charitable Trust, and the Wolpow Family Chair in IBD Treatment and Research. We would like to thank Thaddeus Stappenbeck for providing us Il10rb −/− mice on the C57BL/6 background.