UC Irvine

DRAK2 is a serine/threonine kinase that is differentially expressed during lymphoid development. In vivo mouse models for multiple sclerosis and type 1 diabetes have shown that DRAK2-/- mice display diminished autoimmune susceptibility. Given that DRAK2 acts as a negative regulator of T cell activation, research was been geared toward the mechanism through which it alters autoimmunity. The work in this dissertation was proposed to investigate the mechanism by which DRAK2 alters T cell function and development.

Understanding the mechanisms that control T cell differentiation is crucial to develop novel therapeutic strategies to prevent autoimmune disease. Upon activation, T cells undergo metabolic reprogramming and different T cell subsets utilize selective metabolic pathways. The reason for this reprogramming is that unlike a naïve cell, activated T cells need to generate the necessary biomass and intermediates needed for rapid cell division. Hitherto, the regulating mechanisms promoting the switch from oxidative to glycolytic metabolism have remained elusive. We found that upon SEB stimulation, DRAK2 induces mitochondrial permeability transition pore activity, which allows T cell proliferation and subsequent glycolytic differentiation. This work provides important mechanistic insight into the transient regulation of the mitochondrial permeability transition pore and is the first to identify that this activity can be modulated during metabolic differentiation. Importantly, we show that loss of DRAK2 prevents the expansion of glycolytic cells and that appropriate signal strength, in the context of CD28 costimulation, is sufficient to overcome the characteristic survival defect. These data suggest that CD28 seems to be an important parallel pathway in terms of survival but not necessarily in terms of metabolism. Overall, this work examines the metabolic dysregulation that occurs following loss of DRAK2 in T cells and provides insight into how proliferation and glycolytic differentiation are initiated following activation.