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* Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan;
Research Institute for Diseases of the Chest, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan; and
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
The membrane microdomains known as lipid rafts have been shown to act as platforms for the initiation of various receptor signals. Through proteomic analysis, we have identified a novel protein termed Raftlin (raft-linking protein) as a major protein in lipid rafts. To determine the physiological and immunological functions of Raftlin in mammals, we generated Raftlin-deficient mice, as well as Raftlin-transgenic (Tg) mice. Although Raftlin was originally identified in B cells, we observe no severe abnormalities in the B cells of these mice, presumably due to a high expression of Raftlin-homologue (Raftlin-2). T cells, in contrast, expressed a substantial amount of Raftlin but no Raftlin-2. In Raftlin-deficient mice, T cell-dependent Ab production was reduced, and experimental autoimmune encephalomyelitis, a Th17-dependent autoimmune disease model, was ameliorated. In Raftlin-Tg mice, in contrast, Ab production was enhanced and experimental autoimmune encephalomyelitis was more severe. Cytokine production, especially that of IL-17, was reduced in Raftlin-deficient T cells, while it was enhanced in Raftlin-Tg T cells. We found that these changes were associated with the strength of the TCR-mediated signals. Importantly, localization of Lck protein in the lipid rafts was enhanced by Raftlin overexpression and reduced by Raftlin deficiency. These data indicate that Raftlin modulates TCR signals and is necessary for the fine-tuning of T cell-mediated immune responses.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by special Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), Research Fellowships of the Japan Society for the Promotion of Science (to K.S.), the Takeda Science Foundation, the Kato Memorial Trust for Nambyo Research, the Mitsubishi Pharma Research Foundation, the Naito Foundation, Astellas Foundation for Research on Metabolic Disorders, the Japan Intractable Disease Research Foundation, the Suzuken Memorial Foundation, the Yakult Bioscience Research Foundation and the Princess Takamatsu Cancer Research Fund.
2 Address correspondence and reprint requests to Dr. Akihiko Yoshimura, Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan. E-mail address: yoshimura{at}a6.keio.jp
3 Abbreviations used in this paper: Tg, transgenic; Raftlin, raft-linking protein; WT, wild type; EAE, experimental autoimmune encephalomyelitis; DC, dendritic cell; BMDC, bone-marrow-derived DC; MOG, myelin oligodendrocyte glycoprotein; iTreg, inducible regulatory T cell; TNP, trinitrophenyl; KLH, keyhole limpet hemocyanin; EGFP, enhanced GFP.
4 The online version of this article contains supplementary material.
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