Investigating a novel role of DRAK2 in T cell cytoskeletal regulation and synapse formation.

Abstract

Abstract DRAK2 is a serine/threonine kinase expressed highly in T cells and a potential therapeutic target for autoimmune disease. Drak2 −/−mice are resistant to autoimmune disease in models of type 1 diabetes and multiple sclerosis. This resistance is partly attributed to diminished accumulation of autoreactive T cells in target organs of Drak2 −/−mice. Interestingly, Drak2 −/−T cells can effectively eliminate tumors and pathogens similar to wildtype T cells, which makes DRAK2 an ideal target to inhibit autoreactive, but not pathogen or tumor-specific T cells. Additionally, Drak2 −/−T cells are hypersensitive to suboptimal stimulation, indicating that DRAK2 impacts T cell function. These changes in Drak2 −/−T cell function may be due to alterations in T cell activation, survival, or migration. However, the distinct role of DRAK2 in T cells remains unclear. To address this, we conducted RNA-seq analysis on wildtype and Drak2 −/−T cells at rest and following activation. We identified significant changes in expression of genes within pathways associated with synapse formation, and cytoskeletal regulation. Thus, we examined whether DRAK2 impacts the T cell cytoskeleton or synapse formation. Our data show that Drak2 −/−T cells have significantly reduced polymerized actin, but not monomeric actin compared to wildtype T cells. Additionally, we observed that synapse area was significantly increased while the concentration of TCR in the synapse was decreased in the absence of Drak2. Drak2 −/−T cells also had more malformed synapses and formed fewer conjugates with antigen presenting cells than wildtype T cells. Ongoing experiments will address how DRAK2 mechanistically regulates T cell actin polymerization and synapse formation. Supported by ALSAC and St. Jude Graduate School of Biomedical Sciences.