Glycogen synthase kinase 3β inhibition promotes human iTreg differentiation and suppressive function

Induced regulatory T cells (iTregs) are essential to maintain immunological tolerance, immune homeostasis and prevention of autoimmunity. Some studies suggest that glycogen synthase kinase 3 beta (GSK3 beta) is involved in the mouse iTreg differentiation; however, whether GSK3 beta inhibits or enhances iTreg differentiation is still a matter of controversy. To address this issue, we have utilized human na < ve CD4(+) T cells and investigated whether GSK3 activity changes during iTreg differentiation and whether altering GSK3 activity influences the development of iTregs and its suppressive function. As a constitutively activated kinase, during iTreg differentiation GSK3 beta became quickly deactivated (phosphorylated at serine 9), which is dependent on MAPK pathway rather than PI3-kinase/Akt pathway. Our results indicated that inhibition of GSK3 beta by specific inhibitors, SB216763 or TDZD-8, promoted the differentiation of iTreg and increased their suppressive activity. In contrast, overexpression of GSK3 beta significantly inhibited iTreg differentiation. Furthermore, GSK3 beta inhibition enhanced iTreg differentiation through the TGF-beta/Smad3 pathway. Taken together, this study demonstrates that inhibition of GSK3 beta enhances human iTreg differentiation and its suppressive activity, and provides a rationale to target GSK3 beta as a novel immunotherapeutic strategy.