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| T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17(+) Th cells that cause autoimmune arthritis |
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| Author(s): Hirota K (Hirota, Keiji), Hashimoto M (Hashimoto, Motomu), Yoshitomi H (Yoshitomi, Hiroyuki), Tanaka S (Tanaka, Satoshi), Nomura T (Nomura, Takashi), Yamaguchi T (Yamaguchi, Tomoyuki), Iwakura Y (Iwakura, Yoichiro), Sakaguchi N (Sakaguchi, Noriko), Sakaguchi S (Sakaguchi, Shimon) |
| Source: JOURNAL OF EXPERIMENTAL MEDICINE Volume: 204 Issue: 1 Pages: 41-47 Published: JAN 22 2007 |
| Times Cited: 108 References: 21 |
| 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Sakaguchi, S (reprint author), Kyoto Univ, Inst Frontier Med Sci, Dept Expt Pathol, Kyoto 6068507, Japan |
Addresses:
1. Kyoto Univ, Inst Frontier Med Sci, Dept Expt Pathol, Kyoto 6068507, Japan
2. Univ Tokyo, Inst Med Sci, Ctr Med Expt, Tokyo 1088639, Japan
3. Japan Sci & Technol Agcy, CREST, Kawaguchi 3320012, Japan |
| Publisher: ROCKEFELLER UNIV PRESS, 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA |
| Subject Category: Immunology; Medicine, Research & Experimental |
| IDS Number: 129TS |
| ISSN: 0022-1007 |
| DOI: 10.1084/jem.20062259 |
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