Drak2 and PKD coordinate early T cell activation events to maintain survival (109.24)

Abstract

Abstract T cells deficient in Drak2 hyper-respond to suboptimal stimulation through the antigen receptor, exhibiting enhanced calcium mobilization and high Il-2 production. Despite this lack of negative regulation, mice deficient in Drak2 are resistant to models of induced organ-specific autoimmune disease. This has been attributed in part to a defect in survival following activation, and can be rescued in vitro with exogenous co-stimulation and in vivo through expression of a Bcl-xL transgene. Drak2 kinase activity is crucial to maintain normal calcium responses required for productive activation of T cells, and has recently been shown to require the kinase activity of protein kinase D (PKD). PKD and Drak2 associate at mitochondria, and downstream events are dependent on calcium-induced mitochondrial reactive oxygen generation. PKD and Drak2 are thus part of a critical negative feedback loop whereby calcium influx is both required and targeted by Drak2 activity. Recent work suggests that specific ion channels may be directly targeted by Drak2, with consequences on both the activity of these channels and downstream metabolic events that contribute to proliferative capacity. This implicates both PKD and Drak2 as part of a formerly unappreciated signaling complex that coordinates immediate T cell activation events to limit unproductive activation of T cells and maintain survival.