Structure and Function of the Immunological Synapse

免疫突触的结构和功能

• 批准号: 7019191
• 负责人: Andrey S. Shaw
• 金额: $ 37.35万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7019191
• 关键词: CD2 molecule; CD28 molecule; T cell receptor; T lymphocyte; antigen presentation; antigen presenting cell; biological signal transduction; cell cell interaction; genetically modified animals; immunofluorescence technique; laboratory mouse; leukocyte activation /transformation; membrane activity; phosphorylation; protein degradation; protein localization; protein structure function; protein tyrosine phosphatase; receptor expression; tissue /cell culture

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.

描述（由申请人提供）：T细胞和APC之间接触表面中蛋白质的特定排列称为免疫突触。突触的确切功能尚不清楚，但已提出在TCR信号传导和TCR下调过程中发挥作用。在这里，我们提出了一个模型，该模型表明信号传导，完整的受体磷酸化和下调之间存在复杂的关系。突触中心的募集促进了完全的受体磷酸化，并且完全磷酸化的受体是针对降解的。该模型还表明，无法募集到突触中心的受体仅部分磷酸化，并在去磷酸化后回收到质膜。在此应用中，我们提出了一系列实验，以使用艺术成像技术来检验该假设。具体而言，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。在特定的目标＃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。在特定的目标＃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，在特定目标4中，我们建议检查CD28和CD2在TCR回收和降解中的作用。