T Cell Receptor Signaling by Phosphorylated Forms of TCR

TCR 磷酸化形式的 T 细胞受体信号传导

• 批准号: 7086146
• 负责人: NICOLAI Stanislas Cyrille VAN OERS
• 金额: $ 30.47万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086146
• 关键词: CD3 molecule; Listeria infections; T cell receptor; antigen presentation; biological signal transduction; cellular immunity; developmental immunology; enzyme activity; fluorescence microscopy; genetically modified animals; immune response; immunoregulation; interferon gamma; laboratory mouse; mitogen activated protein kinase; passive immunization; phosphorylation; protein structure function; protein tyrosine phosphatase; three dimensional imaging /topography; video microscopy

DESCRIPTION (provided by applicant): T cells are an essential component of the immune system, recognizing the presence of foreign pathogens and setting in motion very specific intracellular responses to protect the body from serious infection. The T cell receptor (TCR) complex controls these T cell processes. It discriminates very subtle differences in the foreign molecules that it binds to, responding by activating the appropriate intracellular signals that will lead to an effective immune response. The underlying objective of this application is to understand exactly how the T cell receptor controls T cell development and immune functions. This is critical because failure to activate an appropriate response leads to serious infections and inappropriate activation leads to autoimmune diseases. This proposal focuses on the role of the TCRzeta subunit, and the deceptively simple phosphorylation of specific tyrosine residues that is at the core of the TCR's ability to regulate T cell development and immune functions. The TCRzeta subunit forms two discrete tyrosine phosphorylated forms of 21 and 23 kDa (p21 and p23). Preliminary results using a series of transgenic mice that differentially express these phosphorylated proteins indicate that p21 and p23 possess essential non-redundant functions in controlling T cell development, survival, and functions during infections. There are four specific aims in this proposal. The first is to identify the molecular mechanism(s) responsible for the different functions of p21 and p23. The second involves delineating the contribution of p21 to T cell survival. In the third, the functional contribution of phosphorylated zeta to T cells during immune responses to bacterial infections will be determined. The forth aim involves a characterization of phosphatases and kinases that regulate TCR functions. The approaches will incorporate sophisticated biochemical and 3-d imaging studies with the various TCRzeta transgenic lines. The studies will include immunological assays to monitor lymphocyte functions during normal lymphocyte development as well as during infections and autoimmune scenarios.

描述（由申请人提供）：T细胞是免疫系统的重要组成部分，识别外来病原体的存在并启动非常特异的细胞内反应，以保护身体免受严重感染。T细胞受体（TCR）复合体控制这些T细胞过程。它能识别与之结合的外来分子的细微差别，通过激活适当的细胞内信号来做出反应，从而导致有效的免疫反应。本申请的基本目标是准确了解T细胞受体如何控制T细胞发育和免疫功能。这是至关重要的，因为未能激活适当的反应会导致严重的感染，而不适当的激活会导致自身免疫性疾病。该提案集中于TCR ζ亚基的作用，以及特异性酪氨酸残基的看似简单的磷酸化，其是TCR调节T细胞发育和免疫功能的能力的核心。TCRzeta亚基形成21和23 kDa（p21和p23）的两种离散酪氨酸磷酸化形式。使用一系列差异表达这些磷酸化蛋白的转基因小鼠的初步结果表明，p21和p23在控制T细胞发育、存活和感染期间的功能方面具有重要的非冗余功能。这项建议有四个具体目标。首先是确定负责p21和p23不同功能的分子机制。第二个涉及描绘p21对T细胞存活的贡献。在第三，磷酸化ζ的功能贡献T细胞在免疫反应细菌感染将被确定。第四个目标涉及调节TCR功能的磷酸酶和激酶的表征。这些方法将结合复杂的生物化学和三维成像研究与各种TCRzeta转基因系。这些研究将包括免疫学测定，以监测正常淋巴细胞发育期间以及感染和自身免疫情况下的淋巴细胞功能。