TGFβ1通过下调脂肪酸代谢关键酶ACLY蛋白水平促进iTreg细胞分化的作用和机制研究

诱导性调节T细胞（iTreg）是由Th0细胞经诱导分化而来，对维持机体免疫稳态非常重要。TGFβ1是该分化的决定性诱导因子，目前认为其主要通过“TGFβ1-Smad3-Foxp3”调节轴发挥作用。近年来研究发现，在Th0细胞向iTreg细胞分化的过程中发生了由脂肪酸合成代谢向脂肪酸氧化代谢的巨大转变，而且，促进或抑制该代谢转变可极显著地影响iTreg细胞分化。然而，此代谢转变是如何发生的，仍然未知。我们的前期研究表明，TGFβ1在诱导iTreg细胞分化的过程中，可通过下调ATP-柠檬酸裂解酶（ACLY）的蛋白水平实现上述代谢转变。在本项目中，我们拟进一步深入探究TGFβ1下调ACLY蛋白水平的调控机制，并将使用两种小鼠结肠炎模型，在个体水平上对此机制应用于炎症缓解的功效进行评价。本项目力求揭示TGFβ1诱导iTreg细胞分化的新机制，为基于免疫稳态调控的治疗方法和途径提供新思路和新靶标。

iTreg cell (Inducible regulatory T cell) that are derived from Th0 cell play a critical role in the maintenance of immune homeostasis. It is known that TGFβ1 is the determinant inducer of iTreg differentiation and it functions via the well-established “TGFβ1-Smad3-Foxp3” regulatory axis. In recent years, metabolic reprogramming has been linked to iTreg differentiation and a transition from fatty acid synthesis to fatty acid oxidation appears to be essential. Blocking this metabolic transition could result in compromised iTreg differentiation. However, it still remains elusive how this metabolic transition is established. We found that TGFβ1-mediated downregulation in ATP-citrate lyase (ACLY) played an important role in this transition process. This project aims to characterize the regulation of ACLY by TGFβ1 and systematically evaluate the mechanism in two independent mouse models with colitis. By dissecting new mechanism in TGFβ1-mediated iTreg differentiation, we will bring insights into the regulation of immune homeostasis and provide potential targets for the re-balancing of immune system.