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 3β (GSK3β) is involved in the mouse iTreg differentiation; however, whether GSK3β inhibits or enhances iTreg differentiation is still a matter of controversy. To address this issue, we have utilized human naïve 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 GSK3β 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 GSK3β by specific inhibitors, SB216763 or TDZD-8, promoted the differentiation of iTreg and increased their suppressive activity. In contrast, overexpression of GSK3β significantly inhibited iTreg differentiation. Furthermore, GSK3β inhibition enhanced iTreg differentiation through the TGF-β/Smad3 pathway. Taken together, this study demonstrates that inhibition of GSK3β enhances human iTreg differentiation and its suppressive activity, and provides a rationale to target GSK3β as a novel immunotherapeutic strategy.
Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, 300 GuangZhou Road, Nanjing, Jiangsu Province, People's Republic of China.
Yongxiang
Y
Xia
Han
H
Zhuo
Yunjie
Y
Lu
Lei
L
Deng
Runqiu
R
Jiang
Long
L
Zhang
Qin
Q
Zhu
Liyong
L
Pu
Xuehao
X
Wang
Ling
L
Lu
D000328:Adult; D002454:Cell Differentiation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051900:Smad3 Protein / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3