T Cell Receptor Signaling by Phosphorylated Forms of TCR

描述(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，并启动非常特定的细胞内反应，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。它能区分与其结合的外来分子中非常细微的差异，通过激活适当的细胞内信号来做出反应，这将导致有效的免疫反应。这项应用的基本目标是确切地了解T细胞受体如何控制T细胞的发育和免疫功能。这一点至关重要，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。这项建议的重点是TCRzeta亚单位的作用，以及特定酪氨酸残基的简单磷酸化，这是TCR调节T细胞发育和免疫功能的核心。TCRzeta亚基形成两种不同的酪氨酸磷酸化形式，分别为21和23 kDa(p21和p23)。利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细胞的发育、存活和感染期间的功能方面具有基本的非冗余功能。这项提议有四个具体目标。首先是确定p21和p23不同功能的分子机制(S)。第二个涉及描绘p21对T细胞存活的贡献。在第三项研究中，将确定在细菌感染的免疫反应中，磷酸化Zeta对T细胞的功能贡献。第四个目标涉及调节TCR功能的磷酸酶和激酶的特征。这些方法将结合各种TCRzeta转基因品系的复杂生化和3-d成像研究。这些研究将包括免疫分析，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。

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.