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: 6511270
• 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/6511270
• 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)：一种生产性T淋巴细胞反应 抗原需要激活两条信号通路，涉及信号 由T细胞受体(TCR)与抗原相互作用产生 抗原提呈细胞上递呈的多肽及其介导的信号转导 辅助受体CD28与其配体B7的结合。尽管 CD28共刺激的要求一直是密集和 经过广泛的研究，这种共刺激信号的分子性质是 未知。一些模型已经确定了不同的激酶级联反应由 ICR或CD28，而其他模型则专注于 特定激酶上的TCR/CD28信号级联。一条可以调解的途径 CD28共刺激的协同反应的特征是MAP 激酶(ERK)级联。CD28激活MAP激酶ERK的研究 IL-2的产生和反应的增殖需要共刺激 T淋巴细胞。两种拮抗剂对T淋巴细胞ERK活性的调节 小G蛋白：RAS和RAP1。ERK激活需要RAS激活， 而RAP1拮抗RAS信号。外周血中T细胞的抗原识别作用 缺乏CD28共刺激的特征是ERK激活受损和 两者都减少了IL-2的产生，抑制了细胞增殖。此功能 无响应会导致无法对后续 共刺激信号，称为克隆性无能。RAP1是结构性的 在i细胞无能的某些状态下被激活，或者这种无反应可能 导致ERK活性降低和IL-2产生减少的原因 无能T细胞。在这个提案中，我们将测试RAP1是 由ICR连接激活的正常I细胞，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的激活、IL-2的产生和增殖。