The Mechanism Of Glycogen Synthase Kinase 3 Regulates Mature Thymocyte Egress

Glycogen synthase kinase 3(GSK3)has been demonstrated many key roles in glucose metabolism,tissue development and growth,cell differentiation and transmission since it was identified in 1980s.Abnormal activity of GSK3 leads to diabetes,nervous system diseases,cancer and many other diseases.But up to now,little was known about GSK3 in immunology,several lines of evidence indicated that GSK3 was involved in inflammatory response and signal transduction.However,the role of GSK3 in adaptive immunity especially in T cell biology need deeply explored.T cell was a key member in adaptive immunity which present central role in anti-infection immunity,clearance of cancerous or dead cells,and maintaining the host immune homeostasis.T cell numbers,differentiation and function were reply on normal T cell development and export to peripheral lymphoid organs.However,the process is involved in multi-signal transduction and still to be further studied in detail.Here,through a combined genetic and molecular analysis of GSK3,we provide evidence that GSK3 plays a critical role in controlling thymocyte egress and that GSK3 function in this process through an unconventional mechanism of action.Thus,mice with T cell-specific deletion of both GSK3α and GSK3β genes(DKO mice)exhibited a drastic reduction in the numbers of peripheral T cells.Furthermore,we found GSK3-deficient SP thymocytes were more susceptible to apoptosis,accompanied by reduced expression of Bcl-2.However,we also found severely impaired thymocyte egress and homing to lymph nodes in DKO mature thymocytes,this is because DKO single positive(SP)thymocytes failed to upregulate SIP1 and to downregulate CD69,which play a pivotal role in controlling the emigration of mature SP thymocytes from the thymus.Mechanically,GSK3 controls the balance of S1P1 and CD69 expression through the Akt-Foxol-Klf2 signaling pathway.In addition,both constitutively active Foxo1(Foxo1AAA)and inhibition of Akt activity restore emigration of GSK3-deficient thymocytes.Moreover,kinase activity of GSK3 is essential for suppression of Akt activity which controls thymocyte egress.In summary,our study has discovered an essential role of GSK3 in controlling thymocyte egress and survival through suppressing the tonic Akt-Foxol-Klf2 signaling.which can provide a novel sight in controlling the leukemia,immunelogical rejection of tissue transplantation and autoimmune disease.