Date of Award
Doctor of Philosophy (PhD)
Microbial Pathogenesis, Immunology, and Inflammation
Maureen A. McGargill, Ph.D.
Hongbo Chi, Ph.D. Elizabeth A. Fitzpatrick, Ph.D. Tony N. Marion, Ph.D. Brian Sorrentino, M.D.
The immune system utilizes many regulatory mechanisms to limit immune responses and ensure that immune cells target foreign pathogens and not healthy cells of the body. However, some immune cells can escape these checkpoints and attack the body’s healthy cells, leading to tissue destruction and devastating autoimmune disorders. For example, multiple sclerosis (MS) occurs when immune cells attack the myelin sheath surrounding neurons of the central nervous system (CNS). Likewise, the destruction of pancreatic islet cells by dysregulated immune cells leads to type 1 diabetes (T1D). Remarkably, there are more than 80 types of autoimmune diseases. An estimated 50 million Americans suffer from autoimmune disease, and the prevalence continues to increase. These diseases are chronic and potentially life threatening, with associated healthcare costs estimated at $100 billion annually. Current therapies to limit autoimmune diseases often include immunosuppressant medications that also increase susceptibility to infections and tumors. Therefore, therapeutic treatments which specifically inhibit autoreactive immune cells, while sparing immune cells required for pathogen or tumor clearance would significantly improve treatment options.
Drak2, a serine-threonine kinase, expressed abundantly in T and B cells, is a negative regulator of T cell activation. However, unlike other negative regulators, Drak2 plays an important role in eliciting autoimmunity, rather than preventing it. This is demonstrated by the finding that Drak2-/- mice are resistant to autoimmune disease in mouse models of T1D and MS. This resistance is due to reduced accumulation of Drak2-/- autoreactive T cells in the pancreas and CNS compared to wildtype mice. The decreased accumulation of autoreactive T cells in the target organs of Drak2-/- mice is partly due to diminished survival. Interestingly, despite Drak2-/- T cells being more sensitive to death, pathogen clearance and tumor surveillance are maintained in Drak2-/- mice. Therefore, inhibiting Drak2 is a potential alternative therapeutic approach to inhibit autoreactive T cells without suppressing the entire immune system. Thus, there is major interest in identifying the mechanisms by which Drak2 inhibits autoimmunity. This dissertation discusses the current knowledge of Drak2, its role in autoimmunity, and its potential as an inhibitory target to treat disease.
We utilized several in vivo T cell adoptive transfer models to show that resistance to T1D was due to the absence of Drak2 in T cells rather than pancreatic β-cells, and that regulatory T cells (Tregs) were required to elicit resistance. Further analysis revealed that in the absence of Drak2, IL-2 signaling and Treg development increased and likely contributes to disease resistance. We also determined that Drak2 is not a negative regulator of TGF-β signaling in primary T cells, opposing a previous report. Thus it is unlikely that alterations in the TGF-β signaling pathway mediate autoimmune disease resistance in the absence of Drak2. Finally, to advance our understanding of how Drak2 contributes to T cell accumulation, and ultimately to T1D and MS, we established in vitro culture methods to recapitulate the survival defect observed in the absence of Drak2 in vivo. Interestingly, we discovered that Drak2 modifies the actin polymerization pathway either directly or indirectly, and that Drak2-/- T cells exhibited defects in cell cycle progression, proliferation, and other actin-mediated T cell functions that impair T cell accumulation. Together, these data highlight novel insights into the roles of Drak2 in T cell function and autoimmunity, and suggest that subtle changes within these diverse processes may cooperate to contribute to autoimmune disease resistance in the absence of Drak2.
Harris, Tarsha L. , "The Role of Drak2 in T Cell Function and Autoimmunity" (2016). Theses and Dissertations (ETD). Paper 386. http://dx.doi.org/10.21007/etd.cghs.2016.0407.
Available for download on Friday, June 23, 2017