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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.

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