Lipid regulation of T cell receptor transmembrane signaling

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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.