Drak2, a serine/threonine kinase expressed highest in B and T cells, negatively regulates T cell activation. Previously, we showed that Drak2-deficient mice were resistant to disease in models of multiple sclerosis and type I diabetes. Interestingly, these mice were not more susceptible to infection compared to wildtype mice. While this makes Drak2 an ideal protein to target to treat autoimmune disorders without compromising immunity to infectious pathogens, it is still not clear how Drak2 functions to specifically inhibit autoreactive T cells. Here, we report a novel mechanism by which Drak2 impacts autoimmunity. We found that the resistance to type 1 diabetes was due to the absence of Drak2 in the T cells rather than the pancreatic beta cells or other immune cells. Moreover, resistance to disease was dependent on the presence of regulatory T cells (Tregs). Unexpectedly, we found that the development of thymic Tregs was increased in Drak2-deficient mice due to augmented IL-2 signaling, which led to increased proportions of peripheral Tregs compared to wildtype mice. Drak2 limits IL-2 signaling in developing T cells via interaction with Stat5. These data provide important insight into the etiology of autoimmunity by demonstrating that Drak2 not only regulates T cell activation, but also impacts the development of Tregs by regulating IL-2 signaling.

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Drak2 is a serine-threonine kinase expressed most abundantly in T cells and B cells. We previously demonstrated that mice deficient in Drak2 (Drak2-/-) are resistant to disease in models of type 1 diabetes (T1D) and multiple sclerosis (MS) due to a defect in the accumulation of autoreactive T cells. Yet, Drak2-/- mice retain the ability to launch an effective immune response to pathogen infections. Current treatments for autoimmune diseases function by suppressing the immune system, which increases susceptibility to infections and tumors. Thus, Drak2 is a great potential therapeutic target to treat autoimmune disease, because its inhibition may alleviate autoimmune disease without compromising immunity to infections and tumors. Despite its potential as a target, it is unclear how Drak2 regulates the accumulation of autoreactive T cells. Our preliminary data show a decrease in the survival of Drak2-/- T cells compared to wildtype T cells following in vitro stimulation that is rescued by co-culture with wildtype T cells, suggesting a role for Drak2 in production of a critical survival factor. In addition, Drak2-/- T cells display defects in cell cycle progression, morphology, and actin polymerization following activation, implicating a role for Drak2 in the regulation of cytoskeletal dynamics. These data emphasize novel roles for Drak2 in T cell accumulation and suggest that, in the absence of Drak2, T cells exhibit defects in both survival and proliferation.

Mice deficient in the kinase, Drak2, are resistant to disease in mouse models of type 1 diabetes (T1D) and multiple sclerosis (MS) due to diminished survival of autoreactive T cells. Yet, Drak2-/- mice effectively eliminate infectious pathogens and retain the ability to combat tumors similar to wildtype mice. Thus, Drak2 is an ideal protein to target to treat autoimmune disorders without compromising immunity to infections or tumors. However, the molecular mechanisms and functions of Drak2 are unclear. It is important to discern how Drak2 contributes to T1D to further understand the etiology of this disease, as well as to validate Drak2 as a therapeutic target. We show here that the resistance to T1D in NOD.Drak2-/- mice was due to the absence of Drak2 in T cells rather than the pancreatic b-cells. Furthermore, the resistance to disease required regulatory T cells (Tregs). Interestingly, the development of thymic Tregs was increased in Drak2-/- mice due to augmented IL-2 signaling, which led to an increase in the proportion of Foxp3-expressing cells. These studies provide important insight into the etiology of T1D by showing that Drak2 contributes to autoimmune disease by reducing the proportion of Tregs through reduction of IL-2 signaling in T cells.