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

• 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.