Inhibition of CDK2 promotes inducible regulatory T-cell differentiation through TGFβ-Smad3 signaling pathway

• Published in: Cellular immunology Vol. 290; no. 1; pp. 138 - 144
• Main Authors: Gu, Haijuan, Ding, Lixia, Xiong, Si-dong, Gao, Xiao-ming, Zheng, Biao
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.07.2014
• Subjects: Animals; Apoptosis; Benzazepines - pharmacology; CDC2 Protein Kinase - antagonists & inhibitors; CDC2 Protein Kinase - biosynthesis; CDC2 Protein Kinase - genetics; Cell Differentiation - drug effects; Cell Differentiation - immunology; Cell Proliferation; Cells, Cultured; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - biosynthesis; Cyclin-Dependent Kinase 2 - genetics; Cyclin-Dependent Kinase 5 - antagonists & inhibitors; Cyclin-Dependent Kinase 5 - genetics; Foxp3; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta; Indoles - pharmacology; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Phenotypic screening; Receptors, Antigen, T-Cell - immunology; Regulatory T cells; RNA Interference; RNA, Small Interfering; Signal Transduction - immunology; Smad3 Protein - immunology; T-Lymphocytes, Regulatory - immunology; Transcription, Genetic - drug effects; Transforming Growth Factor beta - immunology; Phenotypic screening; Regulatory T cells; Foxp3
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/j.cellimm.2014.05.004

•We have established a phenotypic screening system to find iTreg enhancer and new pathway involving iTreg differentiation.•We have identified that Kenpaullone, potent CDK1, CDK2 and CDK5 inhibitor, can promote iTreg cell differentiation.•We have identified that Kenpaullone promote iTreg cell differentiation through enhancing TGF-b pathway.•We have find that CDK2 is a biological target of Kenpaullone and inhibition of CDK2 can promote iTreg cell differentiation. Inducible regulatory T-cells (iTReg) can be generated from CD4+Foxp3− naïve conventional T-cells by a combination of TGF-β and T-cell receptor (TCR) signaling. It is of enormous clinical importance to identify agents that can promote the generation and differentiation of functional iTreg cells. We have established a phenotypic screening platform to identify new compounds that can promote the TGFβ-mediated iTreg differentiation. We have found Kenpaullone, a potent CDK1, CDK2 and CDK5 inhibitor, as new enhancer for iTreg cell differentiation. Kenpaullone promotes iTreg cell differentiation through increased and prolonged transcription of foxp3 gene by enhancing TGFβ-Smad3 signaling pathway. Thus, we have demonstrated that CDK2 is the biological target of Kenpaullone and proven that CDK2 is a novel negative regulator of iTreg cell differentiation.