Lipid regulation of T cell receptor transmembrane signaling

以T细胞为基础的肿瘤免疫疗法在治疗癌症方面取得了前所未有的成功，但其疗效和应用仍然有限，这就需要对T细胞激活进行更多的机制研究。作为T细胞表面的主要受体，T细胞受体(TCR)识别抗原并将主要的激活信号传递给细胞。Xu和Schamel实验室之前的工作强调了膜脂在调节TCR跨膜信号中的重要性，但其潜在的分子机制尚不清楚。在这里，我们计划结合两个实验室的专业知识，使用最先进的成像、核磁共振、复杂的脂质生物化学和疾病模型。通过这个合作项目，我们旨在了解胆固醇和鞘氨酸甲酯(SM)在质膜中重新分布的时空动力学，胆固醇、SM和TCR跨膜(TM)结构域之间的特定相互作用，以及这些脂蛋白相互作用的功能重要性。该项目的实施将有助于更好地了解T细胞中的主要信号事件，即TCR跨膜信号，也可能导致设计更有效的嵌合抗原受体(CARS)用于癌症免疫治疗。

T cell-based cancer immunotherapies have received unprecedented success in treating cancers but their efficacies and applications are still limited, which calls for more mechanistic studies of T cell activation. As a major receptor on the T cell surface, the T cell receptor (TCR) recognizes antigen and delivers the main activating signal to the cell. Previous works from the Xu and Schamel labs highlight the importance of membrane lipids in regulating TCR transmembrane signaling, but the underlying molecular mechanisms are not well understood. Here we plan to combine the expertise from both labs, using state-of-the-art imaging, nuclear magnetic resonance, sophisticated lipid biochemistry and disease models. With this cooperative project we aim to understand the spatiotemporal dynamics of cholesterol and sphingomeylin (SM) redistribution in the plasma membrane, the specific interactions between cholesterol, SM and TCR transmembrane (TM) domains, as well as the functional importance of these lipid-protein interactions. The performance of this project will lead to better understanding of the major signalling event in T cell, i.e. TCR transmembrane signalling, and might also lead to design more efficient chimeric antigen receptors (CARs) for cancer immunotherapy.