Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation

J Autoimmun. 2013 Feb;40:28-44. doi: 10.1016/j.jaut.2012.07.009. Epub 2012 Aug 24.

Abstract

Compared with its pro-inflammatory function, the mechanisms underlying the anti-inflammatory effect of IL-6 are poorly understood. IL-6 can cooperate with TGF-β to induce IL-10 production in Th17 cells in vitro. However, the effect of IL-6 on generation of Tr1 cells and the in vivo importance of this effect are mostly uncharacterized. In this study, we showed that in vitro, IL-6 can induce the generation of IL-10-producing Tr1 cells from naïve CD4 T cells, independently of IL-27 and TGF-β. IL-6 induces IL-21 production in CD4 T cells and IL-10-inducing effect of IL-6 requires both IL-21 and IL-2. Although IL-6 cannot induce IL-10 production in CD8 T cells in a cell-autonomous manner, it can do so indirectly through promoting CD4 T cell IL-21 production. The IL-10-producing T cells induced by IL-6 have phenotypic, genetic and functional traits of Tr1 cells and can suppress LPS-induced in vivo inflammatory response in an IL-10-dependent fashion. Blockade of IL-6 in two autoimmune inflammation models, induced respectively by anti-CD3 antibody or Treg-depletion, led to reduction in IL-10-producing T cells and exacerbated inflammation of lung and intestine. Thus, we delineated critical pathways involved in IL-6-induced generation of Tr1 cells and demonstrated the importance of this event in restraining autoimmune tissue inflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoimmunity
  • CD3 Complex / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Differentiation
  • Homeodomain Proteins / genetics
  • Inflammation
  • Inflammation Mediators
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism*
  • Interleukin-17
  • Interleukin-2 / metabolism
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism*
  • Interleukins / metabolism
  • Intestines / immunology
  • Lipopolysaccharides
  • Lung / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*

Substances

  • CD3 Complex
  • Homeodomain Proteins
  • Inflammation Mediators
  • Interleukin-17
  • Interleukin-2
  • Interleukin-6
  • Interleukins
  • Lipopolysaccharides
  • RAG-1 protein
  • Interleukin-10
  • interleukin-21