TCF-1和LEF-1协同调控树突状细胞启动滤泡辅助T细胞分化的分子机制研究

滤泡辅助T细胞(TFH)是辅助B细胞产生抗体的细胞亚群，在机体抵御病原体感染和疫苗应答中起关键作用。树突状细胞(DC)是TFH分化的启动者，但调控DC启动TFH细胞分化的转录机制尚不清楚。我们发现，DC细胞活化后转录因子TCF-1显著上调；而将DC敲除TCF-1和LEF-1后，其启动TFH分化的能力明显降低。提示TCF-1和LEF-1在调控DC启动TFH分化中起重要作用。本课题拟利用CD11c-Cre介导的TCF-1和LEF-1条件敲除小鼠在LCMV感染模型中进一步研究TCF-1和LEF-1协同调控DC启动TFH分化的分子机制。寻找启动TFH分化的特异性DC亚群；利用Microarray和ChIP-Seq寻找TCF-1/LEF-1调控的靶基因，并通过回复实验验证；通过检测DC功能分子及定位变化来确定靶基因调控环节。本研究将阐释调控DC细胞启动TFH细胞分化的分子机制，为疫苗设计提供新策略。

Follicular helper T cells (Tfh cells), a unique subset of CD4+ helper T cells, are necessary for B-cell responses and protective vaccines. Dendritic cells initiate the differentiation of TFH cells, but its mechanism remains unclear. We found that TCF-1 is remarkably induced during the activation of dendritic cells，and knock-out TCF-1 and LEF-1 in dendritic cells results in limited TFH differentiation. These data suggests that TCF-1 and LEF-1 are crucial for the initiation of TFH differentiation by dendritic cells. For further investigating the mechanism, we use TCF-1 and LEF-1 conditional knock-out mice and LCMV infection model to detect the differentiation, location and functional molecules expression of dendritic cells. We also use microarray and ChIP-Seq to screen the target genes of TCF-1/LEF-1, and confirm the candidate genes by rescue experiment. And TCF-1 expression can be used as a clue to find specific DC subset to prime TFH cells. This study will explain the mechanism of DC-primed Tfh differentiation and provide important insights into vaccine design.