CX₃CR1⁺ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22

J Exp Med. 2014 Jul 28;211(8):1571-83. doi: 10.1084/jem.20140678. Epub 2014 Jul 14.


Interleukin (IL)-22-producing group 3 innate lymphoid cells (ILC3) promote mucosal healing and maintain barrier integrity, but how microbial signals are integrated to regulate mucosal protection offered by these cells remains unclear. Here, we show that in vivo depletion of CX₃CR1⁺ mononuclear phagocytes (MNPs) resulted in more severe colitis and death after infection with Citrobacter rodentium. This phenotype was rescued by exogenous IL-22, which was endogenously produced by ILC3 in close spatial proximity to CX₃CR1⁺ MNPs that were dependent on MyD88 signaling. CX₃CR1⁺MNPs from both mouse and human tissue produced more IL-23 and IL-1β than conventional CD103(+) dendritic cells (cDCs) and were more efficient than cDCs in supporting IL-22 production in ILC3 in vitro and in vivo. Further, colonic ILC3 from patients with mild to moderate ulcerative colitis or Crohn's disease had increased IL-22 production. IBD-associated SNP gene set analysis revealed enrichment for genes selectively expressed in human intestinal MNPs. The product of one of these, TL1A, potently enhanced IL-23- and IL-1β-induced production of IL-22 and GM-CSF by ILC3. Collectively, these results reveal a critical role for CX₃CR1⁺ mononuclear phagocytes in integrating microbial signals to regulate colonic ILC3 function in IBD.

Publication types

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

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1
  • Citrobacter rodentium / drug effects
  • Citrobacter rodentium / physiology
  • Colitis / immunology*
  • Colitis / microbiology
  • Colitis / pathology*
  • Colitis / prevention & control
  • Dendrites / drug effects
  • Dendrites / metabolism
  • Feces
  • Humans
  • Immunity, Innate* / drug effects
  • Interleukin-1beta / pharmacology
  • Interleukin-23 / metabolism
  • Interleukins / biosynthesis*
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / pathology
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism*
  • Lymphocytes / microbiology
  • Mice
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Phagocytes / drug effects
  • Phagocytes / metabolism*
  • Phagocytes / microbiology
  • Receptors, Chemokine / metabolism*
  • Toll-Like Receptors / metabolism
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / metabolism


  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, human
  • Cx3cr1 protein, mouse
  • Interleukin-1beta
  • Interleukin-23
  • Interleukins
  • Receptors, Chemokine
  • TNFSF15 protein, human
  • Toll-Like Receptors
  • Tumor Necrosis Factor Ligand Superfamily Member 15
  • interleukin-22