CORECEPTOR MODIFICATION OF TCR TYROSINE KINASE SIGNALS

TCR 酪氨酸激酶信号的辅助受体修饰

• 批准号: 6376122
• 负责人: M CARRIE MICELI
• 金额: $ 24.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-08 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6376122
• 关键词: CD28 molecule; T cell receptor; T lymphocyte; antigen presenting cell; biological signal transduction; gene mutation; laboratory mouse; leukocyte activation /transformation; leukocyte adhesion molecules; membrane activity; membrane lipids; phosphorylation; protein tyrosine kinase; tissue /cell culture

DESCRIPTION: (Adapted from applicant's abstract) T cell receptor (TCR) antigen recognition induces the formation and stabilization of a specialized "immunological synapse" at the T cell: antigen presenting cell (APC) junction. This junction is generated by the recruitment and exclusion of particular proteins from the contact area and is required for T cell activation. Advances in cell biology have revealed that the plasma membrane is composed of laterally associated "lipid rafts" which float in a sea of otherwise glycerophospholipid rich membrane. Lipid rafts are enriched in a subset of cellular proteins and have been implicated in signal transduction, cytoskeletal reorganization and protein sorting. We hypothesize that lipid raft/non-raft partitioning provides the molecular basis for protein sorting which organizes the TCR and co stimulators, signal transducers and the actin cytoskeleton at the T cell:APC interface. Our recent studies discriminate two distinctly regulated lipid-raft-dependent T cell activation steps: 1) the TCR engagement-induced phosphorylation and concentration of TCR( and signal transducers within lipid rafts and 2) the TCR/CD48 co stimulation and Lck-SH3-domain-dependent migration of lipid rafts to the TCR contact cap. Whereas T cell activation (TCR induced IL-2 production) requires both steps, T cell inactivation (TCR-induced apoptosis) is unaffected by disruption of the second step. Therefore, we hypothesize that the TCR/mediated-mediated recruitment of lipid rafts to the TCR contact site facilitates the construction of a raft-based platform, which modulates the functional outcome of TCR engagement. To test the role of raft/non-raft membrane compartmentalization in organizing TCR signal transduction and the actin cytoskeleton at the T cell:APC contact cap, we will manipulate the raft/non raft partitioning of proteins involved in these processes and determine the effects on T cell signals and activation (Aim 1). To elucidate the molecular basis of TCR/co stimulation and the relationship between raft reorganization and the functional outcome of TCR engagement we will: a) characterize CD28, CD48 and LFA-1 costimulatory contributions to TCR lipid raft reorganization and signal transduction events (Aim 2); b) explore how subtle differences in TCR antigen binding properties affect antigen-induced raft reorganization, signals and the functional outcome of TCR engagement (Aim 3) and; c) determine if T cells manipulate lipid raft composition and dynamics throughout development to set thresholds for T cell activation (Aim 4). These studies will lead to a better understanding of how TCR signals are regulated to mediate distinct functional outcomes. Elucidation of lipid raft constituents and the molecular mediators of raft reorganization will provide novel targets for therapeutics aimed at independently modulating, individual TCR induced responses such as : 1) inhibiting unwanted T cell activation responsible for autoimmunity, graft rejection, and/or T cell transformation; 2) promoting peripheral tolerance in allograft reactive and autoimmune T cells and 3) potentiating tumor (or other) vaccines directed against sub optimally presented antigens.

描述：（改编自申请人的摘要）T细胞受体（TCR）抗原 识别引起了专业的形成和稳定 T细胞的“免疫突触”：抗原呈现细胞（APC）结。 该交界处是由招募和排除在特定的 接触区域的蛋白质是T细胞激活所必需的。进步 在细胞生物学中，生物学表明质膜由横向组成 相关的“脂质筏”，漂浮在甘油磷脂的海洋中 丰富的膜。脂质筏富集在细胞蛋白的一部分中， 与信号转导，细胞骨架重组和 蛋白质排序。我们假设脂质筏/非羊皮分区提供 组织TCR和CO的蛋白质分类的分子基础 刺激剂，信号传感器和T细胞的肌动蛋白细胞骨架：APC 界面。我们最近的研究区分了两个明显的调节 脂质依赖性T细胞激活步骤：1）TCR参与诱导 TCR的磷酸化和浓度（脂质内的信号传感器 筏和2）TCR/CD48 CO刺激和LCK-SH3核心依赖性迁移 脂质筏的TCR接触盖。而T细胞激活（TCR诱导 IL-2产生）都需要两个步骤，T细胞灭活（TCR诱导 凋亡）不受第二步的破坏影响。因此，我们 假设TCR/介导的脂质筏募集到 TCR接触站点促进了基于筏的平台的构建，该平台 调节TCR参与的功能结果。测试角色 组织TCR信号中的木筏/非生育膜隔室化 T细胞处的转导和肌动蛋白细胞骨架：APC接触帽，我们将 操纵与这些蛋白的筏/非筏分配 过程并确定对T细胞信号和激活的影响（AIM 1）。 阐明TCR/CO刺激的分子基础和关系 在筏重组和TCR参与的功能结果之间 WILL：a）表征CD28，CD48和LFA-1的COTORMINTOVINE对TCR的贡献 脂质筏的重组和信号转导事件（AIM 2）； b）探索 TCR抗原结合特性的细微差异如何影响抗原诱导的 RAFT重组，信号和TCR参与的功能结果（AIM 3）and; c）确定T细胞是否操纵脂质筏组成和动力学 在整个开发过程中，为T细胞激活设定阈值（AIM 4）。这些 研究将使人们更好地了解如何调节TCR信号 介导不同的功能结果。阐明脂筏成分 RAFT重组的分子介体将提供新的目标 对于旨在独立调节的治疗剂，单个TCR诱导 诸如：1）抑制不需要的T细胞激活负责的响应 自身免疫性，移植排斥和/或T细胞转化； 2）促进 同种异体移植反应性和自身免疫性T细胞中的外周耐受性以及3） 针对亚副介绍的增强肿瘤（或其他）疫苗 抗原。