CD45 REGULATION OF T LYMPHOCYTE ACTIVATION

CD45 对 T 淋巴细胞激活的调节

• 批准号: 2903423
• 负责人: DAVID LEITENBERG
• 金额: $ 16.89万
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2903423
• 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（改编自研究者摘要）：T细胞的连接 抗原受体（TcR）不导致单一系列事件，而是 会导致各种不同的结果，包括扩散， 细胞毒性，细胞凋亡，淋巴因子分泌的不同模式，以及无反应性。 负责调节这些不同结果的精确机制 仍然不清楚。在调节T细胞活化中重要的一种分子是CD 45， 一个高分子量跨膜糖蛋白家族，由 含有蛋白酪氨酸磷酸酶活性的胞质尾区，和 可变的外部结构域编码在三个外显子中， 由于转录后选择性RNA剪接， 至少八种不同亚型的表达。CD 45亚型表达 T淋巴细胞在胸腺发育过程中受到不同的调节， 外周T细胞活化和分化，并与不同的 效应器功能。 提示CD 45的胞外域可以调节T细胞增殖， 在抗原活化过程中的信号传导途径。支持这一假设的是 观察到表达低分子量CD 45同种型细胞 与细胞相比， 表达高分子量同种型，这与 单个低分子量CD 45同种型与细胞因子结合的能力 CD 4/T细胞受体复合物。我们假设不同的胞外域 CD 45的同种型可以调节底物进入酪氨酸磷酸酶 通过将CD 45靶向到膜中的不同区域， 与T细胞信号转导中的其他重要分子结合， 改变它们的磷酸化状态并改变TcR信号转导 通路使用生物化学和遗传学方法相结合， 转染的T细胞系和原代CD 4 T细胞中，研究者将 在本提案中处理以下问题：1.规则和机制 CD 45与T细胞受体复合物的结合;和2.生化 以及CD 45与T细胞受体结合的生物学后果。 对CD 45在T细胞活化中作用的理解增加， 应用到不同的功能特性的天真，记忆和 效应T细胞亚群以及T细胞功能的变化相关 随着年龄的增长。此外，关于T细胞活化调节的基础研究 在癌症发病机理、自身免疫、 传染病