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Regulation of T-cell and antigen-presenting cell interactions by Rapl.

Rapl 对 T 细胞和抗原呈递细胞相互作用的调节。

基本信息

批准号：
12670300
负责人：
HATTORI Masakazu
金额：
$ 2.24万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670300/
关键词：
Rap1 SPA- 1 T cell anergy apoptosis p27kip1 アポプトーシス P27kip1 FAS Rap1GAP APC LFA-1 ICAM-1 Spa-1

项目摘要

Activation of T cells by antigen requires adhesive interactions with antigen-presenting cells (APC) in which leukocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecules (ICAMs) are important. However, it is not well understood what signaling molecules regulate this process and how the modulation of adhesive events influences T-cell activation. Here we show that Rap1 is activated in T cells in an antigen-dependent manner and accumulated at the contact site of T-cell and antigen-loaded APC. Inhibition of Rap1 activation by a dominant-negative Rap1 or SPA-1, a Rapl GTPase-activating protein, abrogates LFA-1-ICAM-1-mediated adhesive interactions with antigen-pulsed APC and the subsequent T-cell-receptor triggering and interleukin-2 production. Conversely, augmented antigen-dependent Rap1 activation by the expression of wild-type Rap1 enhances these responses but culminates in apoptosis by Fas and FasL. Thus, Rap1 functions as a key regulator of T-cell and APC interactions and modulates T-cell responses from productive activation to activation-induced cell death by regulating the strength of adhesive interactions. Moreover, constitutive Rap1 activation rendered T cells unresponsive with accumulation of p27(Kip1). Our study indicates that the activation state of Rap1 has a decisive effect on the T-cell response to antigen.

抗原激活T细胞需要与抗原呈递细胞（APC）的粘附相互作用，其中白细胞功能相关抗原1（LFA-1）和细胞间粘附分子（ICAM）是重要的。然而，目前还不清楚是什么信号分子调节这一过程，以及粘附事件的调节如何影响T细胞活化。在这里，我们表明，Rap 1在T细胞中以抗原依赖性的方式被激活，并在T细胞和抗原负载的APC的接触部位积累。显性阴性Rap 1或SPA-1（Rap 1 GTP酶激活蛋白）对Rap 1激活的抑制消除了LFA-1-ICAM-1介导的与抗原脉冲APC的粘附相互作用以及随后的T细胞受体触发和白细胞介素-2产生。相反，增强抗原依赖性Rap 1激活野生型Rap 1的表达增强这些反应，但最终在凋亡Fas和FasL。因此，Rap 1作为T细胞和APC相互作用的关键调节因子发挥作用，并通过调节粘附相互作用的强度来调节T细胞从生产性活化到活化诱导的细胞死亡的反应。此外，组成性Rap 1激活使T细胞对p27（Kip 1）的积累无反应。我们的研究表明Rap 1的激活状态对T细胞对抗原的反应具有决定性影响。