The small G protein Rap 1 in T cell activation/anergy

T 细胞激活/无反应中的小 G 蛋白 Rap 1

• 批准号: 6632272
• 负责人: PHILIP J.S. STORK
• 金额: $ 30.2万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632272
• 关键词: CD28 molecule; CD3 molecule; T cell receptor; T lymphocyte; anergy; genetically modified animals; guanine nucleotide binding protein; guanosinetriphosphatases; interleukin 2; laboratory mouse; leukocyte activation /transformation; mitogen activated protein kinase; protein biosynthesis; tissue /cell culture; transfection

DESCRIPTION (Provided by the Applicant): A productive T lymphocyte response to antigen requires the activation of two signaling pathways, involving signals generated by the interactions between the T-cell receptor (TCR) with antigenic peptide presented on antigen-presenting cells (APCs) and the signal mediated by the binding of the accessory receptor CD28 with its ligand B7. Although the requirement for CD28 co-stimulation has been the subject of intensive and extensive investigation, the molecular nature of this co-stimulatory signal is unknown. Some models have identified distinct kinase cascades initiated by either the ICR or CD28, while other models have focused on the convergence of TCR/CD28 signals on particular kinase cascades. One pathway which can mediate the synergistic responses that characterize CD28 co-stimulation is the MAP kinase (ERK) cascade. The activation of the MAP kinase ERK following CD28 co-stimulation is required for IL-2 production and proliferation of responding T lymphocytes. ERK activation in T lymphocytes is regulated by two antagonistic small G proteins: Ras and Rap1. Ras activation is required for ERK activation, while Rap1 antagonizes Ras signaling. Antigen recognition by T-cells in the absence of CD28 co-stimulation is characterized by impaired ERK activation and both decreased IL-2 production and diminished proliferation. This functional unresponsiveness results in the inability to respond to subsequent co-stimulatory signals and is termed clonal anergy. Rap1 is constitutively activated in certain states of I cell anergy or this unresponsiveness may account for the diminished ERK activity and decreased IL-2 production seen in anergic T-cells. In this proposal, we will test the hypothesis that Rap1 is activated by ICR ligation in normal I cells and consequently limits I cell activation through the ICR in the absence of co-stimulation. In addition, we will test the hypothesis that CD28 co-stimulation achieves increased ERK activation, IL-2 production and proliferation by blocking Rap1 activation.

描述（由申请人提供）：生产性 T 淋巴细胞对 抗原需要激活两条信号通路，涉及信号 由 T 细胞受体 (TCR) 与抗原之间的相互作用产生 抗原呈递细胞（APC）上呈递的肽及其介导的信号 辅助受体 CD28 与其配体 B7 的结合。虽然 CD28 共刺激的要求一直是深入研究的主题 经过广泛的研究，这种共刺激信号的分子性质是 未知。一些模型已经鉴定出由以下因素引发的不同激酶级联： ICR 或 CD28，而其他模型则侧重于融合 特定激酶级联上的 TCR/CD28 信号。一种可以调解的途径 表征 CD28 共刺激的协同反应是 MAP 激酶 (ERK) 级联。 CD28 之后 MAP 激酶 ERK 的激活 IL-2 的产生和反应细胞的增殖需要共刺激 T淋巴细胞。 T 淋巴细胞中的 ERK 激活受到两种拮抗作用的调节 小 G 蛋白：Ras 和 Rap1。 ERK 激活需要 Ras 激活， 而 Rap1 则拮抗 Ras 信号传导。 T细胞对抗原的识别 CD28 共刺激缺失的特点是 ERK 激活受损 两者均减少了 IL-2 的产生并减少了增殖。这个功能性的 反应迟钝导致无法响应后续 共刺激信号，被称为克隆无能。 Rap1 是本构型 在 I 细胞无反应性的某些状态下被激活，或者这种无反应可能 解释了 ERK 活性减弱和 IL-2 产生减少的原因 无反应性 T 细胞。在这个提案中，我们将测试 Rap1 的假设 在正常 I 细胞中通过 ICR 连接激活，从而限制 I 细胞 在没有共刺激的情况下通过 ICR 激活。此外，我们 将检验 CD28 共刺激实现 ERK 增加的假设 通过阻断 Rap1 激活、IL-2 产生和增殖。