The Tumor Necrosis Factor Superfamily Member RANKL Suppresses Effector Cytokine Production in Group 3 Innate Lymphoid Cells

Immunity. 2018 Jun 19;48(6):1208-1219.e4. doi: 10.1016/j.immuni.2018.04.012. Epub 2018 May 29.


While signals that activate group 3 innate lymphoid cells (ILC3s) have been described, the factors that negatively regulate these cells are less well understood. Here we found that the tumor necrosis factor (TNF) superfamily member receptor activator of nuclear factor κB ligand (RANKL) suppressed ILC3 activity in the intestine. Deletion of RANKL in ILC3s and T cells increased C-C motif chemokine receptor 6 (CCR6)+ ILC3 abundance and enhanced production of interleukin-17A (IL-17A) and IL-22 in response to IL-23 and during infection with the enteric murine pathogen Citrobacter rodentium. Additionally, CCR6+ ILC3s produced higher amounts of the master transcriptional regulator RORγt at steady state in the absence of RANKL. RANKL-mediated suppression was independent of T cells, and instead occurred via interactions between CCR6+ ILC3s that expressed both RANKL and its receptor, RANK. Thus, RANK-RANKL interactions between ILC3s regulate ILC3 abundance and activation, suggesting that cell clustering may control ILC3 activity.

Publication types

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

MeSH terms

  • Animals
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Immunity, Innate / immunology*
  • Lymphocyte Subsets / immunology*
  • Lymphocyte Subsets / metabolism
  • Mice
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / biosynthesis
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • RANK Ligand / immunology*
  • RANK Ligand / metabolism
  • Receptors, CCR6 / immunology


  • CCR6 protein, mouse
  • Cytokines
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RANK Ligand
  • Receptors, CCR6
  • Tnfsf11 protein, mouse