急性和慢性病毒感染中TCF1/LEF1对滤泡调节性T细胞(Tfr)PD-1表达的调控及其对Tfr分化的影响

滤泡调节性T细胞(Tfr)分化自调节性T细胞(Treg)，表达Bcl-6和Foxp3，其分化受PD-1的调控。Wnt信号转录因子TCF1/LEF1可调控Bcl-6表达和Treg功能，还具有组蛋白修饰功能，但在Tfr分化中的作用尚不清楚。我们前期发现Treg特异的TCF1/LEF1缺失下调PD-1的表达，其机制与TCF1直接结合在PD-1基因位点有关。因此推测在免疫反应中TCF1/LEF1可通过转录调节及组蛋白修饰的方式调控PD-1的表达，并调节Tfr的分化。本项目拟针对Foxp3介导的TCF1/LEF1敲除小鼠建立急性和慢性病毒感染模型，研究病毒感染中TCF1/LEF1对Tfr分化的调控作用，以PD-1的表达调节为切入点探讨Tfr分化中转录调节和组蛋白修饰对基因表达的调控。本项目的开展将有助于揭示TCF1/LEF1对Tfr分化的调控机制，并为以PD-1或Tfr为目标的治疗策略提供参考。

Follicular regulatory T cells (Tfr) express Bcl-6 and Foxp3, which are master regulators of follicular helper T cells (Tfh) and regulatory T cells(Treg), respectively. Treg are precusors of Tfr. PD-1 controls the differentiation and function of Tfr. Recent study showed that TCF1/LEF1, downstream transcription factors of wnt signal, could initiate Bcl-6 expression during acute infection. Additionally, TCF1/LEF1 exhibit intrinsic histone deacetylase activity at the late stage of T cell development. Preliminary data showed that specific ablation of TCF1/LEF1 in Treg cells results in decreased expression of PD-1, and ChIP results showed that TCF1 binds to the upstream of transcription start site at PD-1 gene locus. Therefore, we hypothesize that TCF1/LEF1 regulate Tfr differentiation through both transcriptional and epigenetic modification of PD-1 expression during viral infection. This project aims to investigate the regulation of TCF1/LEF1 on PD-1 expression of Tfr and Tfr differentiation during acute and chronic viral infection, using Foxp3-cre mediated TCF1/LEF1 conditional knockout mice. This research will elucidate the regulation of wnt signal on Tfr differentiation, and provide new insights into therapeutic applications targeting PD-1 or Tfr cells for the treatment of infectious diseases.