A Major Lipid Raft Protein Raftlin Modulates T Cell Receptor Signaling and Enhances Th17-Mediated Autoimmune Responses
A Major Lipid Raft Protein Raftlin Modulates T Cell Receptor Signaling and Enhances Th17-Mediated Autoimmune Responses
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DOI：
10.4049/jimmunol.0802672
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发表时间：
2009-05-15
影响因子：
4.4
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Saeki, Kazuko;Fukuyama, Satoru;Yoshimura, Akihiko
被称为脂筏的膜微域已被证明可以作为各种受体信号启动的平台。通过蛋白质组学分析，我们发现了一种称为 Raftlin（筏连接蛋白）的新型蛋白质，它是脂筏中的主要蛋白质。为了确定 Raftlin 在哺乳动物中的生理和免疫功能，我们生成了 Raftlin 缺陷小鼠以及 Raftlin 转基因（Tg）小鼠。尽管 Raftlin 最初是在 B 细胞中发现的，但我们在这些小鼠的 B 细胞中没有观察到严重异常，这可能是由于 Raftlin 同源物 (Raftlin-2) 的高表达所致。相比之下，T 细胞表达大量 Raftlin，但不表达 Raftlin-2。在 Raftlin 缺陷小鼠中，T 细胞依赖性抗体产生减少，实验性自身免疫性脑脊髓炎（一种 Th17 依赖性自身免疫性疾病模型）得到改善。相反，在 Raftlin-Tg 小鼠中，抗体产生增强，实验性自身免疫性脑脊髓炎更加严重。 Raftlin 缺陷型 T 细胞中细胞因子的产生，尤其是 IL-17 的产生减少，而 Raftlin-Tg T 细胞中的细胞因子产生增加。我们发现这些变化与 TCR 介导的信号强度相关。重要的是，Lck 蛋白在脂筏中的定位因 Raftlin 过度表达而增强，并因 Raftlin 缺乏而减少。这些数据表明 Raftlin 调节 TCR 信号，对于 T 细胞介导的免疫反应的微调是必要的。免疫学杂志，2009，182：5929-5937。
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 Journal of Immunology, 2009, 182: 5929-5937.