Structure and Function of the Immunological Synapse

描述(由申请人提供)：T细胞和APC之间接触面上蛋白质的特殊排列称为免疫突触。突触的确切功能尚不清楚，但已被认为在TCR信号传递过程中发挥作用，并对TCR下调起作用。在这里，我们提出了一个模型，该模型表明信号、完全受体磷酸化和下调之间存在复杂的关系。重新聚集到突触中心促进了全面的受体磷酸化，而完全磷酸化的受体是降解的目标。该模型还表明，无法被招募到突触中心的受体仅部分被磷酸化，并在去磷酸化后循环到质膜。在这一应用中，我们提出了一系列实验，使用最先进的成像技术来验证这一假设。具体地说，在特定的目标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。在特定目标#2中，我们建议确定完全磷酸化的受体与部分磷酸化的受体的磷酸化位置。在具体目标#3中，我们建议研究受体下调在胸腺细胞信号转导中的作用。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.