接头蛋白BCAP在树突状细胞发育分化及差异化调节免疫应答中的作用及机制

The adaptor protein BCAP involves in regulating the development and function of macrophage, NK cell and B cell. Notably, BCAP regulates distinct signaling pathways in different cell types, suggesting that it exerts a cell-specific further. Intriguingly, although T cell doesn’t express BCAP protein, the proportion of effector/memory T cells in the BCAP-KO resting mice is higher than wild-type mice. This indicates that BCAP may indirectly affect T cell function via regulating DC maturation. Our previous study demonstrated that BCAP-KO mice had attenuated humoral immune response and increased inflammation-obvious inflammation in the organ of aged BCAP-KO mice. What’s more, we also found that BCAP is involved in regulating DC maturation including phenotype and function. It inhibited and feedback regulated the NF-κB and PI3K pathway through the dynamic interaction with MyD88. While, on the other hand, BCAP showed another function model in the MyD88-independent signal pathway, which suggests that in the MyD88-dependent or –independent signals, BCAP functions as a selector to regulate different pathways. In this study, the effects of BCAP regulating signaling pathways and its functions on DC development and immune responses will be further investigated; especially the mechanisms of selective regulation of signals and maintaining the homeostasis in DC response to immune stimulus.

接头蛋白BCAP通过调控PI3K、NF-κB等信号通路，分别在巨噬、NK和B细胞的分化和免疫应答中起到细胞特异性的调控作用。虽然T细胞不表达BCAP，但BCAP-KO小鼠中效应T细胞增多，提示BCAP可能通过调节树突状细胞（DC）的成熟活化，影响了T细胞的分化，而BCAP在DC中的作用却仍一无所知。本实验室前期研究发现，BCAP-KO小鼠体液免疫减弱，炎症反应增强；老龄化小鼠脏器有明显炎症；BCAP-KO BMDC的成熟分化表型和功能异常。体外实验发现，BCAP可同时开启及反馈调节NF-κB和PI3K信号通路；同时，对Toll样受体介导的免疫应答表现出以MyD88依赖和非依赖为区别的差异反应。据此，本项目拟以DC特异性BCAP缺陷小鼠为模型，深入研究BCAP在DC前体细胞分化发育及活化成熟中的作用和机制，特别是对不同诱导因子来源信号通路的差异反应，及维持DC免疫应答过程中稳态的作用和机制。

对免疫细胞发育分化以及免疫应答调节网络的研究，有助于深入了解细胞调控的分子机制，为免疫细胞的开发应用奠定基础。本研究主要探讨了 BCAP 基因对树突状细胞前体发育，以及不同分化途径来源 iDC 的调控作用和机制；以及巨噬细胞和自然杀伤细胞通过免疫应答和迁移调节肿瘤转移的分子机制。揭示了树突状细胞对不同诱导因子来源信号通路的差异反应，以及BCAP分别 与MyD88和PI3K相互作用，双向调节NK-kB和PI3K通路，动态调节和维持树突状细胞在免疫反应中的活化和稳态的一个全新的细胞维持自身稳态的调节网络。另一项研究阐述了肺局部巨噬细胞和自然杀伤细胞通过细胞因子相互作用，调节细胞迁移和免疫应答，在肿瘤细胞转移上起到重要作用。课题研究期间共发表SCI论文2篇，参加国内、外会议交流报告3余次，培养博士研究生2人、硕 士研究生1人，全面完成了课题计划和任务。