CD45 REGULATION OF T LYMPHOCYTE ACTIVATION

CD45 对 T 淋巴细胞激活的调节

• 批准号: 6171072
• 负责人: DAVID LEITENBERG
• 金额: $ 17.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171072
• 关键词: CD antigens; T cell receptor; biological signal transduction; calcium flux; cell differentiation; cytokine; helper T lymphocyte; leukocyte activation /transformation; phosphorylation; protein biosynthesis; protein tyrosine kinase; receptor binding; tissue /cell culture

DESCRIPTION (Adapted from Investigator's Abstract): Ligation of the T cell antigen receptor (TcR) does not result in a single series of events but rather can lead to a wide variety of different outcomes including proliferation, cytotoxicity, apoptosis, distinct patterns Of lymphokine secretion, and anergy. The precise mechanisms responsible for regulating these different outcomes remain unclear. One molecule important in regulating T cell activation is CD45, a family of high molecular weight transmembrane glycoproteins consisting of a cytoplasmic tail containing protein tyrosine phosphatase activity, and a variable external domain encoded in three exons which are differentially expressed due to post-transcriptional alternative RNA splicing, resulting in the expression of at least eight different isoforms. CD45 isoform expression on T lymphocytes is differentially regulated during thymic development and peripheral T cell activation and differentiation, and correlates with distinct effector functions. This suggests the hypothesis that the ectodomain of CD45 can regulate T cell signaling pathways during antigen activation. In support of this hypothesis is the observation that cells that express low molecular weight CD45 isoforms exhibit increased responsiveness to antigen signaling compared to cells expressing high molecular weight isoforms, and that this correlates with the ability of individual low molecular weight CD45 isoforms to associate with the CD4/T cell receptor complex. We hypothesize that the different ectodomain isoforms of CD45 may regulate substrate access to the tyrosine phosphatase domains by targeting CD45 to distinct areas in the membrane where it can associate with other molecules important in T cell signal transduction, altering their phosphorylation status and modifying the TcR signal transduction pathway. Using a combination of biochemical and genetic approaches in transfected T cell lines and in primary CD4 T cells, the investigator will address the following issues in this proposal: 1. The regulation and mechanism of CD45 association with the T cell receptor complex; and 2. The biochemical and biological consequences of CD45 association with the T cell receptor. Increased understanding of the role of CD45 in T cell activation has direct application to the different functional characteristics of naive, memory and effector T cell subsets as well as the changes in T cell function associated with aging. In addition basic studies on the regulation of T cell activation have broad applicability to fields of cancer pathogenesis, autoimmunity, and infectious disease.

描述(摘自《研究人员摘要》)：T细胞的连接 抗原受体(TCR)不会导致一系列事件，而是 可能会导致各种各样的不同结果，包括扩散， 细胞毒性，细胞凋亡，淋巴因子分泌的不同模式，以及无能。 调控这些不同结果的确切机制 目前仍不清楚。调节T细胞活化的一个重要分子是CD45， 一族高相对分子质量的跨膜糖蛋白，由一个 胞质尾部含有蛋白酪氨酸磷酸酶活性，以及 编码在三个不同外显子中的可变外部结构域 由于转录后选择性RNA剪接而表达，导致 至少八种不同亚型的表达。CD45异构体的表达 T淋巴细胞在胸腺发育过程中的差异调节 外周T细胞的激活和分化，并与不同的 效应器功能。 这表明CD45的胞外结构域可以调节T细胞的假设 抗原激活过程中的信号通路。支持这一假设的是 表达低分子量CD45的细胞亚型的观察 与细胞相比，表现出对抗原信号的更高反应 表达高分子量异构体，这与 单个低分子量CD45亚型与血管内皮生长因子结合的能力 CD4/T细胞受体复合体。我们假设不同的外星域 CD45的亚型可能调节底物对酪氨酸磷酸酶的访问 通过将CD45靶向于膜上的不同区域 与T细胞信号转导中重要的其他分子结合， 改变它们的磷酸化状态和修饰TCR信号转导 路径。使用生化和遗传方法的组合 在转基因T细胞系和原代CD4T细胞中，研究人员将 解决本方案中的以下问题：1.法规和机制 CD45与T细胞受体复合体的结合；2.生化 以及CD45与T细胞受体相关的生物学后果。 对CD45在T细胞激活中的作用的了解的增加直接 应用于幼稚、记忆和记忆的不同功能特征 效应性T细胞亚群及其相关T细胞功能的变化 随着年龄的增长。此外，T细胞活化调节的基础研究 广泛应用于癌症发病机制、自身免疫和 传染病。