Suppressive Treg Cell Activity Is Potentiated by Glycogen Synthase Kinase 3β Inhibition

The mechanism by which regulatory T cells (Tregs) suppress the immune response is not well defined. A recent study has shown that β catenin prolongs Treg survival. Since β-catenin is regulated by GSK-3β directed phosphorylation, we focused on GSK-3β and the role it plays in Treg function. Inhibition of GSK-3β leads to increased suppression activity by Tregs. Inhibitor-treated Tregs exhibited prolonged FoxP3 expression and increased levels of β -catenin and of the anti-apoptotic protein, Bcl-XL. Systemic administration of GSK-3β inhibitor results in prolonged islet survival in an allotransplant mouse model. Our data suggest GSK-3β could be a useful target in developing strategies designed to increase the stability and function of Tregs for inducing allotransplant tolerance or treating autoimmune conditions. Regulatory T cells (Tregs) are charged with the important task of maintaining homeostatic T cell reactivity and are thought to prevent autoimmunity by restraining self-reactive T cells that escape thymic deletion (1,2). Moreover, Treg cells have been shown to downregulate all T cell driven immunity (3,4), which is of increasing interest in the transplant community. However, expansion of Tregs has proved challenging due to their anergic potential. While some studies have shown induction of CD4+CD25+ Treg cells from CD4+CD25cells with various exogenous cytokines or peptides (5-7), their functional profile may not be the same as that of naturally occurring CD4+CD25+ Treg cells (8). This difference has given impetus to those searching for a method to improve CD4+CD25+ Treg cell stability and activity. http://www.jbc.org/cgi/doi/10.1074/jbc.M110.150904 The latest version is at JBC Papers in Press. Published on August 20, 2010 as Manuscript M110.150904