A mechanistic understanding of Dynein mediated centrosomal translocation in activated T cells

Abstract

Our adaptive immune system is capable of detecting and removing foreign invaders but also unhealthy cancerous and virally-infected human cells. This process depends on strictly regulated intracellular T cell receptor (TCR) signalling cascades and subsequent centrosomal polarization and targeted cytolytic granule release. Advancements in our molecular understanding of early TCR signalling have led us to immunotherapies, such as CAR-T, which mobilize and support T cells to our advantage, however new challenges consciously arise. Interestingly, in contrast to early-TCR signalling, very little is known about how T cells polarize and mediate targeted cytolytic granules release. Dynein is central to translocating the centrosome and cytolytic granules from around the cell to their destination for targeted cell death. Yet, how dynein is regulated, recruited and activated in activated T cells is unknown. Here, we propose a comprehensive study in which we cover the identification of the dynein interactome during T cell activation, functionally characterize novel dynein regulators required for centrosomal polarization and recapitulate dynein-mediated polarization in primary human CAR-T cells.