DRAK2 contributes to type 1 diabetes by negatively regulating IL-2 sensitivity to alter regulatory T cell development
Alexandra H. Mandarano, Tarsha Harris, Blaine Creasy, Marie Wehenkel, Marygrace Duggar, Benjamin A. Wilander, Ashutosh Mishra, Jeremy Chase Crawford, Sarah A. Mullen, Katherine M. Williams, M. R. A. Pillai, Anthony A. High, Maureen A. McGargill
Abstract
Drak2 -deficient ( Drak2 −/− ) mice are resistant to multiple models of autoimmunity yet effectively eliminate pathogens and tumors. Thus, DRAK2 represents a potential target to treat autoimmune diseases. However, the mechanisms by which DRAK2 contributes to autoimmunity, particularly type 1 diabetes (T1D), remain unresolved. Here, we demonstrate that resistance to T1D in non-obese diabetic ( NOD ) mice is due to the absence of Drak2 in T cells and requires the presence of regulatory T cells (T regs ). Contrary to previous hypotheses, we show that DRAK2 does not limit TCR signaling. Rather, DRAK2 regulates IL-2 signaling by inhibiting STAT5A phosphorylation. We further demonstrate that enhanced sensitivity to IL-2 in the absence of Drak2 augments thymic T reg development. Overall, our data indicate that DRAK2 contributes to autoimmunity in multiple ways by regulating thymic T reg development and by impacting the sensitivity of conventional T cells to T reg -mediated suppression.