Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function

Immunity. 2014 May 15;40(5):706-19. doi: 10.1016/j.immuni.2014.03.011. Epub 2014 May 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cell Differentiation / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Colitis, Ulcerative / genetics*
  • Colitis, Ulcerative / immunology*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Humans
  • Immune Tolerance / genetics
  • Immune Tolerance / immunology
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Inflammation / immunology
  • Interleukin-10 / immunology*
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Interleukin-10 / deficiency
  • Receptors, Interleukin-10 / genetics
  • Receptors, Interleukin-10 / immunology*
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / immunology


  • DNA-Binding Proteins
  • IL10 protein, mouse
  • Rag2 protein, mouse
  • Receptors, Interleukin-10
  • Interleukin-10