Structure and Function of the Immunological Synapse

描述（由申请人提供）：T细胞和APC之间的接触表面中蛋白质的特定排列被称为免疫突触。突触的确切功能尚不清楚，但已提出其在TCR信号传导过程中起作用，并且还用于TCR下调。在这里，我们提出了一个模型，表明有一个复杂的信号之间的关系，完全受体磷酸化和下调。募集到突触中心促进完全受体磷酸化，并且完全磷酸化的受体被靶向降解。该模型还表明，不能被募集到突触中心的受体仅部分磷酸化，并在去磷酸化后再循环到质膜。在这个应用中，我们提出了一系列的实验来测试这个假设，使用最先进的成像技术。具体而言，在具体目标#1中，我们建议分析突触形成、受体磷酸化和受体降解之间的关系。在具体目标#2中，我们建议确定完全磷酸化与部分磷酸化受体的磷酸化位点。在特定目标#3中，我们建议检查受体下调在胸腺细胞信号传导中的作用。最后，在具体目标#4中，我们建议检查CD28和CD2在TCR再循环和降解中的作用。

DESCRIPTION (provided by applicant): The specific arrangement of proteins in the contact surface between the T cell and the APC is known as the immunological synapse. The exact function of the synapse is not clear but it has been proposed to function in the process of TCR signaling and also for TCR downregulation. Here we propose a model that suggests that there is a complex relationship between signaling, full receptor phosphorylation and down-regulation. Recruitment to the center of the synapse facilitates full receptor phosphorylation, and fully phosphorylated receptors are targeted for degradation. The model also suggests that receptors that are unable to be recruited to the center of the synapse become only partially phosphorylated and are recycled to the plasma membrane after dephosphorylation. In this application, we propose a series of experiments to test this hypothesis using state of the art imaging techniques. Specifically, in Specific Aim # 1, we propose to analyze the relationship between synapse formation, receptor phosphorylation and receptor degradation. In Specific Aim #2, we propose to determine the site of phosphorylation of fully phosphorylated versus partially phosphorylated receptors. In Specific Aim #3, we propose to examine the role of receptor downregulation in thymocyte signaling. Lastly, in Specific Aim #4, we propose to examine the role of CD28 and CD2 in TCR recycling and degradation.