Investigating a novel role of DRAK2 in T cell migration and synapse formation - Project Summary Autoimmune disease is a rising threat that affects over 24 million Americans. Many of the current therapies for the over 80 distinct autoimmune diseases seek to broadly suppress the immune system. However, this leads to many deleterious effects and leaves patients at risk for development of infection and cancer. There is an urgent need to develop therapeutics that selectively inhibit the autoreactive immune response without compromising immunity to pathogens and tumors. However, we lack a complete understanding of molecular pathways that differentially impact autoreactive and pathogen-specific T cells. DRAK2 is a serine/threonine kinase expressed highly in lymphocytes. Drak2-/- mice are resistant to disease in mouse models of type 1 diabetes and multiple sclerosis. Resistance to these autoimmune diseases is partly due to reduced accumulation of T cells in the target organs of Drak2-/- mice compared to wildtype mice. However, Drak2-/- mice maintain the ability to effectively clear tumors and pathogens similar to wildtype mice, and Drak2-/- T cells are able to enter peripheral organs in response to pathogens. Thus, DRAK2 functions in a signaling pathway that differentially impacts autoreactive and pathogen-specific T cells. However, the distinct roles of DRAK2 on T cell activation, migration, and function remain unclear. A further understanding of how DRAK2 impacts T cell function will provide essential insight into molecular pathways distinctly affecting autoreactive and pathogen-specific T cells, which is critical in order to develop improved therapies for autoimmune diseases. To fill this gap in knowledge, I will evaluate the role of DRAK2 in critical aspects of T cell migration and synapse formation, which are essential for optimal T cell activation. My preliminary data demonstrate that genes associated with migration, synapse formation, and actin regulation are differentially expressed in T cells in the absence of Drak2. Additionally, Drak2-/- T cells display decreased migration to the chemokine, CCL19 and abnormal synapse morphology compared to wildtype T cells. Thus, I hypothesize that DRAK2 regulates T cell synapse formation and migration, which impairs optimal T cell activation. To address this hypothesis, in Aim 1, I will assess T cell migration in the absence of Drak2 by evaluating chemokine receptor surface expression, migration to chemokines, actin protrusion formation, and in vivo migration. In Aim 2, I will determine if synapses formed between Drak2-/- T cells and antigen presenting cells differ in size, kinetics, or organization compared to wildtype T cells. Together, these studies will investigate how DRAK2 alters the critical T cell functions of migration and synapse formation. Further insight into the role of DRAK2 in T cell activation and function will reveal pathways that differentially impact autoreactive and pathogen- specific T cells, which will provide important information for developing novel therapeutic targets to treat autoimmune disease.
