WASP缺陷促进T-bet高表达非典型记忆B细胞分化的机制研究

非典型记忆B细胞(aMBCs)被认为是一类耗竭状态的记忆B细胞亚群，具有高表达T-bet及其他表型特征，其分化机制尚不清楚。既往研究提示IFNγ诱导T-bet过度表达可能是调控aMBCs分化的重要机制。WAS患儿有体液免疫缺陷，我们前期发现WAS患儿T-bet高表达aMBCs增多，WAS患儿及WASKO小鼠CD4+T细胞激活后分泌IFNγ增多，且WAS患儿B细胞经IFNγ刺激后，aMBCs数量增加。故我们提出假设，WASP缺陷导致IFNγ过多分泌，反复刺激诱导B细胞T-bet表达，使其BCR抑制信号增强，不能进入生发中心而形成大量aMBCs。本研究拟首先验证WAS患儿aMBCs功能，进一步解析WASP通过BCR相关负性调控影响aMBCs分化机制，阐明aMBCs形成对体液免疫的影响。本研究属原创性研究，可为WAS体液免疫缺陷提供新机制，更可为相关疾病的精准防治和优化疫苗设计提供部分理论基础。

Atypical memory B cells (aMBCs) was considered as an exhausted subset of memory B cells with high expression of T-bet. However, the differentiation mechanism of the aMBCs remains unknown. It has been reported that interferons gamma(IFNγ) driving T-bet "overexpression" may play a role in aMBC differentiation. Our previous study have found that WAS patients with a significantly increase in T-bet hi aMBCs, which may be one of the reasons for the immune deficiency in WAS. Then, We found IFNγ secreted by activated CD4+T cells was increased in WAS patients and WASKO mice, and the number of aMBCs was significantly increased with IFNγ stimulation in WAS patients. So we hypothesized that WASP defects leads to excessive IFNγ repeated stimulation, which induce T-bet expression in B cells and inhibit BCR signaling, that drive naïve B cells differentiate into aMBCs instead of entering germinal center. This study is focus on the function and differentiation mechanism of aMBCs. The results may remind new mechanism of immune deficiency in WAS, it will also provide new clues for precise treatment of WAS patients and the design of the vaccine.