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      Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction

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          Abstract

          In autoimmune arthritis, traditionally classified as a T helper (Th) type 1 disease, the activation of T cells results in bone destruction mediated by osteoclasts, but how T cells enhance osteoclastogenesis despite the anti-osteoclastogenic effect of interferon (IFN)-γ remains to be elucidated. Here, we examine the effect of various Th cell subsets on osteoclastogenesis and identify Th17, a specialized inflammatory subset, as an osteoclastogenic Th cell subset that links T cell activation and bone resorption. The interleukin (IL)-23–IL-17 axis, rather than the IL-12–IFN-γ axis, is critical not only for the onset phase, but also for the bone destruction phase of autoimmune arthritis. Thus, Th17 is a powerful therapeutic target for the bone destruction associated with T cell activation.

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          A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.

          Heon Park, Zhaoxia Li, Xuexian O. Yang … (2005)
          Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.
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            Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.

            Daniel Cua, Jonathan P Sherlock, Yi. Chen … (2003)
            Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.
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              Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.

              T R Mosmann, H Cherwinski, M Bond … (1986)
              A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Exp Med
                Title: The Journal of Experimental Medicine
                Publisher: The Rockefeller University Press
                ISSN (Print): 0022-1007
                ISSN (Electronic): 1540-9538
                Publication date (Print): 27 November 2006
                Volume: 203
                Issue: 12
                Pages: 2673-2682
                Affiliations
                [1 ]Department of Cell Signaling, [2 ]Department of Oral Pathology, Graduate School, and [3 ]COE Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
                [4 ]Department of Human Pathology and [5 ]Department of Orthopaedic Surgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
                [6 ]Department of Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan
                [7 ]Department of Host Defence, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
                [8 ]Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
                [9 ]Discovery Research, DNAX Research Inc., Palo Alto, CA 94304
                [10 ]Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Agency (JST), Saitama 332-0012, Japan
                Author notes

                CORRESPONDENCE Hiroshi Takayanagi: taka.csi@ 123456tmd.ac.jp

                Article
                Publisher ID: 20061775
                DOI: 10.1084/jem.20061775
                PMC ID: 2118166
                PubMed ID: 17088434
                SO-VID: 8894ed04-3902-4e02-96d5-2e67426c80f7
                Copyright © Copyright © 2006, The Rockefeller University Press
                History
                Date received : 18 August 2006
                Date accepted : 12 October 2006
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                Subject: Articles
                Subject: Article

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