title: T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis.
abstract: This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17-secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologically resembles rheumatoid arthritis (RA). The thymus-produced self-reactive T cells, which become activated in the periphery via recognition of major histocompatibility complex/self-peptide complexes, stimulate antigen-presenting cells (APCs) to secrete IL-6. APC-derived IL-6, together with T cell-derived IL-6, drives naive self-reactive T cells to differentiate into arthritogenic Th17 cells. Deficiency of either IL-17 or IL-6 completely inhibits arthritis development, whereas interferon (IFN)-gamma deficiency exacerbates it. The generation, differentiation, and persistence of arthritogenic Th17 cells per se are, however, insufficient for producing overt autoimmune arthritis. Yet overt disease is precipitated by further expansion and activation of autoimmune Th17 cells, for example, via IFN-gamma deficiency, homeostatic proliferation, or stimulation of innate immunity by microbial products. Thus, a genetically determined T cell self-reactivity forms a cytokine milieu that facilitates preferential differentiation of self-reactive T cells into Th17 cells. Extrinsic or intrinsic stimuli further expand these cells, thereby triggering autoimmune disease. Intervention in these events at cellular and molecular levels is useful to treat and prevent autoimmune disease, in particular RA.
authors.affiliation: Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hirota
authors.forename: Motomu
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoshitomi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakaguchi
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology*; D002454:Cell Differentiation; D016207:Cytokines / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma