Molecular basis of type2 helper T cell differentiation reading to lgE production

2型辅助T细胞分化解读lgE产生的分子基础

• 批准号: 10670311
• 负责人: NAKAYAMA Toshinori
• 金额: $ 2.05万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670311/
• 关键词: Th1; Th2; Ras; MARK cascade; allergy; T cell receptor; IL-4; ヘルパーT細胞; ドミナントネガティブ

The central role of Type-2 helper T (Th2) cells in the development of allergic responses and immune responses against helminthic parasites is well documented. The differentiation of Th2 cells from naive T cells requires both the recognition of antigen by T-cell antigen receptors (TCR) and the activation of downstream signal transduction molecules of the IL-4 receptor (IL-4R) pathway, including Jak1, Jak3, and STAT6. Little is known, however, about how these two distinct pathways cooperate with each other to induce Th2 cells. Here we use a T cell specific H-ras-dominant negative transgenic mouse to show that TCR-mediated activation of Ras/Mitogen-activated protein kinase (MAPK) pathway alters IL-4R function and is required for Th2 cell differentiation. The enhancement of IL-4R signaling appears to be a consequence of both direct crosstalk with the TCR signaling pathway and increased protein expression of downstream signaling molecules of the IL-4R pathway. Therefore, successful Th2 differentoation depends on the effectiveness of the TCR-mediated activation of the Ras/MAPK pathways in modifying the IL-4R-mediated signaling pathway. In another words, we present evidence that the TCR-mediated Ras/MAPK activation controls IL4R-mediated signaling and determines the direction of helper T cell differentiation. Thus, our data suggest that the lineage choices made by naive Th cells following antigen, stimulation are clearly influenced by.

2型辅助性T（Th 2）细胞在针对蠕虫寄生虫的过敏反应和免疫反应的发展中的中心作用被充分记载。从初始T细胞分化Th 2细胞需要T细胞抗原受体（TCR）识别抗原和激活IL-4受体（IL-4 R）途径的下游信号转导分子，包括Jak 1、Jak 3和STAT 6。然而，很少有人知道这两种不同的途径如何相互合作，以诱导Th 2细胞。在这里，我们使用T细胞特异性H-ras显性阴性转基因小鼠，以显示TCR介导的Ras/丝裂原活化蛋白激酶（MAPK）途径的激活改变IL-4 R的功能，是所需的Th 2细胞分化。IL-4 R信号传导的增强似乎是与TCR信号传导途径的直接串扰和IL-4 R途径的下游信号传导分子的蛋白质表达增加的结果。因此，成功的Th 2分化取决于TCR介导的Ras/MAPK通路活化在修饰IL-4 R介导的信号传导通路中的有效性。换句话说，我们提出的证据表明，TCR介导的Ras/MAPK激活控制IL 4 R介导的信号转导，并决定了辅助性T细胞分化的方向。因此，我们的数据表明，抗原刺激后幼稚Th细胞的谱系选择明显受到。

项目成果

Sato, H., Nakayama, T., Tanaka, Y., Yamashita, M., Shibata, Y., Kondo, E., Saito, Y., and Taniguchi, M.: "Induction of differentiation of pre-NKT cells to mature Va14 NKT cells by GM-CSF."Proc. Natl. Acad. Sci. USA. 96. 7439-7444 (1999)

Sato, H.、Nakayama, T.、Tanaka, Y.、Yamashita, M.、Shibata, Y.、Kondo, E.、Saito, Y. 和 Taniguchi, M.：“前 NKT 细胞分化的诱导

Kaneko, Y., Harada, M., Kawano, T., Yamashita, M., Shibata, Y., Geiyo, F., Nakayama, T., and Taniguchi M.: "Augmentation of Va14 NKT Cell-mediated Cytotoxicity by IL-4 in an Autocrine Mechanism Resulting in the Development of Concanavalin A-induced Hepati

Kaneko, Y.、Harada, M.、Kawano, T.、Yamashita, M.、Shibata, Y.、Geiyo, F.、Nakayama, T. 和 Taniguchi M.：“增强 Va14 NKT 细胞介导的细胞毒性

Kubo, M.: "T cell receptor stimulation and CD28 costimulation increases IL-4 receptor sensitivity: A requirement for Th2 differentiation"J. Immunol.. 163. 2432-2442 (1999)

Kubo, M.：“T 细胞受体刺激和 CD28 共刺激增加 IL-4 受体敏感性：Th2 分化的要求”J.

Yamashita,M.: "Requirement for p56^<lck> tyrosine kinase activation in T helper subset differentiation." Int.Immunol.10. 577-591 (1998)

Yamashita,M.：“T 辅助细胞亚群分化中 p56^<lck> 酪氨酸激酶激活的要求。”

Nakayama,T.: "TCR-mediated signal transduction pathways that control helper T cell differentiation:Requirement for activation of Lck tyrosine kinase and Ras/MAPK pathway in Th2 cell differentiation." 10th International congress of in Immunology. Internati

Nakayama,T.：“控制辅助 T 细胞分化的 TCR 介导的信号转导途径：Th2 细胞分化中激活 Lck 酪氨酸激酶和 Ras/MAPK 途径的要求。”