IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB

J Immunol. 2017 Oct 1;199(7):2333-2342. doi: 10.4049/jimmunol.1601554. Epub 2017 Aug 25.

Abstract

Group 3 innate lymphoid cells (ILC3s) are important regulators of the immune system, maintaining homeostasis in the presence of commensal bacteria, but activating immune defenses in response to microbial pathogens. ILC3s are a robust source of IL-22, a cytokine critical for stimulating the antimicrobial response. We sought to identify cytokines that can promote proliferation and induce or maintain IL-22 production by ILC3s and determine a molecular mechanism for this process. We identified IL-18 as a cytokine that cooperates with an ILC3 survival factor, IL-15, to induce proliferation of human ILC3s, as well as induce and maintain IL-22 production. To determine a mechanism of action, we examined the NF-κB pathway, which is activated by IL-18 signaling. We found that the NF-κB complex signaling component, p65, binds to the proximal region of the IL22 promoter and promotes transcriptional activity. Finally, we observed that CD11c+ dendritic cells expressing IL-18 are found in close proximity to ILC3s in human tonsils in situ. Therefore, we identify a new mechanism by which human ILC3s proliferate and produce IL-22, and identify NF-κB as a potential therapeutic target to be considered in pathologic states characterized by overproduction of IL-18 and/or IL-22.

MeSH terms

  • Cell Proliferation*
  • Dendritic Cells / physiology
  • Humans
  • Immunity, Innate
  • Interleukin-15 / immunology
  • Interleukin-18 / metabolism*
  • Interleukin-22
  • Interleukins / biosynthesis*
  • Interleukins / genetics
  • Interleukins / immunology
  • Lymphocytes / physiology*
  • NF-kappa B / metabolism*
  • Palatine Tonsil / cytology
  • Palatine Tonsil / immunology
  • Promoter Regions, Genetic
  • Signal Transduction* / immunology
  • Transcription Factor RelA / metabolism

Substances

  • IL15 protein, human
  • IL18 protein, human
  • Interleukin-15
  • Interleukin-18
  • Interleukins
  • NF-kappa B
  • Transcription Factor RelA