Experimental and clinical studies highlight the potential for T cells in enhancing anti-tumor response and their pathological role in inflammation. Thus, efforts aimed at understanding the signal transduction mechanisms utilized during T cell activation provide a foundation for developing strategies to pharmacologically or genetically enhance or suppress T cell functions when needed. The actin cytoskeleton and its regulators play a key role in T-cell receptor (TCR)-, costimulatory-, and integrin-mediated signaling. Our preliminary data suggest that the dynamic interaction of three actin-regulatory proteins, Dynamin 2, Vav1 and WAVE2 influence cytoskeletal changes and the activation of kinase cascades following TCR engagement. The mechanistic experiments outlined in this proposal will functionally characterize the role of Dyn2 and its effector molecules in actin-mediated processes following TCR crosslinking by testing the central hypothesis that: Dyn2 contributes to T cell activation by functioning as a molecular scaffold for the assembly of actin regulatory proteins at the T cell - ARC contact site. In addition, we propose that the novel Dyn2-Vav1 interaction is required for the localization of Vav1 to the immunological synapse where it will activate its target molecule Rac1. Moreover, we provide evidence that identifies a role for the Rac1-regulated WAVE2 complex as a target of Dyn2 that plays a key role in T cell activation. In order to test our central hypothesis, we will (1) Determine the role of Dynamin 2 in T cell activation;(2) Determine the mechanism by which Vav1 regulates Dynamin 2-mediated regulatory events;and (3) Determine the role of the Abi-WAVE2 complex in T cells. Together, these studies will provide an experimental basis for understanding the molecular events that are involved in the regulation of T cell activation, and will in a broader context, advance our understanding of fundamental processes involved in actin cytoskeletal dynamics during lymphocyte activation.
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