IL-6-dependent spontaneous proliferation is required for the induction of colitogenic IL-17-producing CD8+ T cells

J Exp Med. 2008 May 12;205(5):1019-27. doi: 10.1084/jem.20071133. Epub 2008 Apr 21.


We propose a novel role for interleukin (IL) 6 in inducing rapid spontaneous proliferation (SP) of naive CD8(+) T cells, which is a crucial step in the differentiation of colitogenic CD8(+) T cells. Homeostasis of T cells is regulated by two distinct modes of cell proliferation: major histocompatibility complex/antigen-driven rapid SP and IL-7/IL-15-dependent slow homeostatic proliferation. Using our novel model of CD8(+) T cell-dependent colitis, we found that SP of naive CD8(+) T cells is essential for inducing pathogenic cytokine-producing effector T cells. The rapid SP was predominantly induced in mesenteric lymph nodes (LNs) but not in peripheral LNs under the influence of intestinal flora and IL-6. Indeed, this SP was markedly inhibited by treatment with anti-IL-6 receptor monoclonal antibody (IL-6R mAb) or antibiotic-induced flora depletion, but not by anti-IL-7R mAb and/or in IL-15-deficient conditions. Concomitantly with the inhibition of SP, anti-IL-6R mAb significantly inhibited the induction of CD8(+) T cell-dependent autoimmune colitis. Notably, the transfer of naive CD8(+) T cells derived from IL-17(-/-) mice did not induce autoimmune colitis. Thus, we conclude that IL-6 signaling is crucial for SP under lymphopenic conditions, which subsequently caused severe IL-17-producing CD8(+) T cell-mediated autoimmune colitis. We suggest that anti-IL-6R mAb may become a promising strategy for the therapy of colitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoimmune Diseases / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Division
  • Colitis / immunology*
  • DNA-Binding Proteins / deficiency
  • Immunologic Memory
  • Interleukin-17 / biosynthesis*
  • Interleukin-6 / immunology*
  • Kinetics
  • Major Histocompatibility Complex
  • Mice
  • Mice, Knockout


  • DNA-Binding Proteins
  • Interleukin-17
  • Interleukin-6
  • Rag2 protein, mouse