The Mechanism Of Glycogen Synthase Kinase 3 Maintains Regulatory T Cell Homeostasis And Function

Glycogen synthase kinase3(GSK3)is a serine/threonine protein kinase that regulates several cellular processes,such as cell proliferation,stem cell renewal,apoptosis,but is not well-known in T cell biology.Our studies have demonstrated that mice with T cell-specific deletion of both GSK3α and GSK3β(DKO mice)exhibited a drastic reduction in the cell numbers of T cells in peripheral lymphoid organs.Though these data demonstrated the key role of GSK3 in early T cell development and egress,it is limited to explore the function of GSK3 in peripheral T cell differentiation and Treg cell function because lack of the T cells in the periphery.Here we reported that GSK3 is essential for Treg cell homeostasis and function.We generated mice with GSK3α and GSK3β deletion by using OX40 promoter-mediated Cre expression in activated CD4+T and Treg cells.GSK3 deficient(DKO)mice exhibited a significantly shorter lifespan and loss of body weight.Moreover,DKO mice had splenomegaly and lymphadenopathy,severe infiltration of immune cells in multiple organs,spontaneous T cell activation and increased production of the pro-inflammatory cytokine interferon(IFN-y)by CD4+and CD8+T cells.Mechanistically,GSK3 deficiency resulted in impaired Treg cell homeostasis and function via regulating Akt/Foxo1 axis,but does not affect Treg cell development and differentiation.GSK3 deficiency caused increased Akt activity,Foxo1 phosphorylation and ubiquitination in Treg cells after TCR stimulation.Expression of constitutively active form of Foxo1(FoxolAAA)in Treg cells partially rescued autoimmune disease caused by GSK3 deficiency.Taken together,GSK3 signaling in Treg cells controls Treg cell homeostasis and maintains their function,thereby orchestrating the balance between immunity and tolerance.Our study made progress in the molecular mechanism of Treg cells,and provided a new therapeutic direction for a new drug design in Treg cells for the treatment of tumors and autoimmune diseases.