The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20071133
The Journal of Experimental Medicine, Vol. 205, No. 5, 1019-1027
The Rockefeller University Press, 0022-1007 $30.00
© Tajima et al.
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BRIEF DEFINITIVE REPORT

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

Masaki Tajima1, Daiko Wakita1, Daisuke Noguchi1, Kenji Chamoto1, Zhang Yue3, Kazunori Fugo4, Harumichi Ishigame2, Yoichiro Iwakura2, Hidemitsu Kitamura1, and Takashi Nishimura1,3

1 Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
2 Center for Experimental Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
3 Division of ROYCE' Health Bioscience, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 001-0021, Japan
4 Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan

CORRESPONDENCE Takashi Nishimura: tak24{at}igm.hokudai.ac.jp

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.

© 2008 Tajima et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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