Signaling by the serine/threonine kinase Drak2 in T cells (35.23)

Abstract

Abstract A role for Drak2 in negative regulation of T cell activation has been well established, yet the manner in which Drak2 mediates downstream events to limit the spurious activation of T cells remains to be elucidated. While T cells from mice deficient in Drak2 exhibit a decreased activation threshold and hyper-respond to sub-optimal stimuli, the proliferative capacity of these cells is diminished as result of a deficiency in survival. A resistance to the induction of EAE in Drak2-deficient mice underscores a dependence on negative regulatory molecules to enforce the requirement of co-stimulation to engage an effective immune response. Biochemical data tracking Drak2 activation has revealed that protein kinase D (PKD) is required for Drak2 signaling. PKD has been shown to respond to the release of calcium from intracellular stores as well as to oxidative stress, two events coupled to T cell activation through the processes of IP3R-mediated ER-calcium depletion and increased mitochondrial respiration. The signaling requirements of Drak2 similarly include both store-operated calcium entry and the production of reactive oxygen species. The data presented indicate that Drak2 and PKD constitute a signaling axis that defines a novel role for PKD in T cell activation and further sheds light on how Drak2 orchestrates decreased responsiveness as a negative regulatory molecule.