BCL6/TCF1信号在WASp缺陷所致记忆B细胞前体细胞形成及分化失衡中的作用及机制研究

典型记忆B细胞(MBCs)和非典型记忆B细胞(aMBCs)生成的失衡是Wiskott-Aldrich综合征(WAS)导致感染和自身免疫的重要环节，但机制不清楚。生发中心B细胞通过下调B淋巴细胞瘤6(BCL6)分化形成MBCs的前体细胞；MBCs前体细胞具有向典型MBCs和aMBCs二元分化的命运，而T细胞因子1(TCF1)上调是促进典型MBCs形成的关键。我们前期发现：WAS小鼠MBCs前体细胞形成增加伴生发中心B细胞BCL6表达下降；MBCs前体细胞TCF1表达下降伴aMBCs生成增加。结合核内WAS蛋白(WASp)是调控其他细胞BCL6、TCF1转录的关键因子的发现，据此推测：BCL6/TCF1信号是介导WASp缺陷所致的MBCs前体细胞形成和分化失衡的关键因素。本研究拟进一步利用WASp核定位信号序列缺失的小鼠并结合体内实验，为阐明WAS导致MBCs形成异常的机制提供新线索。

The Wiskott-Aldrich syndrome (WAS) is a rare X-linked latent genetic immunodeficiency disease, which is caused by the mutation of WAS gene encoding WAS protein (WASp). Intrinsic defects of memory B cells (MBCs) are predominant in WAS patients with decreased classical MBCs and expanded atypical MBCs (aMBCs), which are directly contributory to the reduced protection from infections and prevalent autoimmune disorders, respectively. The mechanisms remain incompletely defined, which hinder the application of targeted therapies..It has been characterized a population of germinal centre (GC) B cells differentiating into MBCs, identified as MBC precursors, preceded by down-regulation of B-Cell Lymphoma 6 (BCL6) . T cell factor-1 (TCF1) can act as a master regulator of the bifurcated fate of classical MBCs and aMBCs from MBC precursors. In our previous study we got some detailed clues that is WASp deficiency affects the development step from GC B cells to the MBC precursors stage via BCL6, and the following balanced differentiation between classical MBCs and aMBCs through TCF1 during acute virus infection. .It has been identified that nuclear WASp can play an important role in hematopoietic cells differentiation by cytoskeleton independent mechanisms and control transcription factors including BCL6 and TCF1. So we hypothesized that WASp controls GC-derived MBC precursors development and differentiation through BCL6 and TCF1 at different stages. Conditional nuclear localization signal-like motif of WASp knockout mouse model was used to explore the mechanism, which will help to clarify the role of WASp in the balanced generation of MBCs, and may provide new clues for clinical interventions.