Structure and Function of the Immunological Synapse

描述（由申请人提供）：蛋白质在T细胞和APC之间的接触面上的特定排列被称为免疫突触。突触的确切功能尚不清楚，但已提出它在TCR信号传导过程中起作用，也参与TCR下调。在这里，我们提出了一个模型，表明在信号，全受体磷酸化和下调之间存在复杂的关系。突触中心的招募促进了受体的完全磷酸化，而完全磷酸化的受体是降解的目标。该模型还表明，不能被募集到突触中心的受体仅被部分磷酸化，并在去磷酸化后再循环到质膜。在这个应用程序中，我们提出了一系列的实验来测试这一假设，使用最先进的成像技术。具体来说，在Specific Aim # 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Specific Aim #2中，我们建议确定完全磷酸化和部分磷酸化受体的磷酸化位点。在Specific Aim #3中，我们建议研究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，我们建议研究CD28和CD2在TCR回收和降解中的作用。

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.