IL-6-dependent spontaneous proliferation is required for the induction of colitogenic IL-17-producing CD8+ T cells.
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.
Tajima
Masaki
M
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Wakita
Daiko
D
Noguchi
Daisuke
D
Chamoto
Kenji
K
Yue
Zhang
Z
Fugo
Kazunori
K
Ishigame
Harumichi
H
Iwakura
Yoichiro
Y
Kitamura
Hidemitsu
H
Nishimura
Takashi
T
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division; D003092:Colitis / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency; D007156:Immunologic Memory; D020381:Interleukin-17 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000276:immunology*; D007700:Kinetics; D008285:Major Histocompatibility Complex; D051379:Mice; D018345:Mice, Knockout
D004268:DNA-Binding Proteins; D020381:Interleukin-17; D015850:Interleukin-6; C499308:Rag2 protein, mouse