新型化合物组合抑制STAT6维持Foxp3-CNS2去甲基化产生稳定的iTreg细胞诱导小鼠肾移植免疫耐受的机制研究

iTreg细胞是诱导肾移植免疫耐受的理想策略，但iTreg细胞Foxp3-CNS2甲基化，不表达Foxp3，导致细胞失去稳定性和抑制功能，这是利用iTreg细胞诱导耐受的关键障碍。我们筛选发现一种新型化合物组合（3C），成功诱导稳定的有抑制功能的抗原特异性iTreg细胞（3C-iTreg细胞）（AJT,2020）。初步研究发现，3C促进CNS2去甲基化和Foxp3表达，且抑制STAT6核激活和与CNS2结合。据此提出假说，3C抑制STAT6维持Foxp3-CNS2去甲基化，促进了Foxp3表达，产生稳定的iTreg细胞诱导肾移植免疫耐受。为验证该假说，拟明确3C-iTreg细胞在肾移植小鼠体内的存活、功能和诱导耐受的作用，研究3C促进CNS2去甲基化和Foxp3表达的机制。本研究将探明增强iTreg细胞稳定性和抑制功能的新机制、新方法，为临床利用iTreg细胞诱导疫耐受提供理论依据。

iTreg cells are an ideal strategy for maintaining immune tolerance. Foxp3-CNS2 methylation in iTreg cells inhibits Foxp3 expression, resulting in poor cell stability and inhibitory function. It is still a huge challenge to maintain CNS2 demethylation and Foxp3 stable expression. We recently discovered that a compounds combination (3C) promoted CNS2 demethylation and Foxp3 expression, thereby generating stably existing iTreg cells with inhibitive function (3C-iTreg cells) (AJT, 2020). Further research found that 3C inhibited STAT6 nuclear activation and its binding to CNS2. Based on this, it is hypothesized that 3C can maintain Foxp3-CNS2 demethylation to generate iTreg cells via inhibition of STAT6, thereby inducing immune tolerance in kidney transplantation. To verify this hypothesis, it is decided to clarify the survival, function of 3C-iTreg cells and its role in inducing immune tolerance in vivo, and to explore the molecular mechanism of 3C promoting CNS2 demethylation and Foxp3 expression. This study will reveal the molecular mechanism of 3C inducing stable iTreg cells with inhibitive function, and provide a theoretical basis for clinical use of iTreg cells to induce immune tolerance.