Gao Fangjie, Yang Yuanyuan, Wang Zhengyi, Gao Xiaoming, Zheng Biao
Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
Cell Immunol. 2015 Mar;294(1):1-8. doi: 10.1016/j.cellimm.2015.01.010. Epub 2015 Jan 28.
Germinal center (GC) reaction is a T cell-dependent process in which activated B cells undergo clonal expansion and functional maturation to produce high affinity antibodies and differentiate into memory B cells(1). Here we demonstrate a new role of bromodomain and extraterminal domain (BET) protein BRD4 in GC B cell development. We found that during B cell differentiation stage there was an elevated expression of BRD4 in GC B cells and inhibition of BRD4 by small molecule inhibitors led to the suppression of GC formation and correspondent antibody responses in a Td antigen immunization model. At the molecular level, we found that the effects of BRD4 in primary GC B cell differentiation and B cell lymphoma were mediated through the impaired phosphorylation and translocation of NF-κBp65 and further down-regulation of B-cell lymphoma 6 (Bcl6) expression. Thus this study reveals a novel function of BRD4 in controlling the GC B cell development pathway.
生发中心（GC）反应是一个T细胞依赖的过程，在此过程中，活化的B细胞经历克隆扩增和功能成熟，以产生高亲和力抗体并分化为记忆B细胞(1)。在此，我们证明了含溴结构域和额外末端结构域（BET）蛋白BRD4在GC B细胞发育中的新作用。我们发现，在B细胞分化阶段，GC B细胞中BRD4的表达升高，在Td抗原免疫模型中，小分子抑制剂对BRD4的抑制导致GC形成和相应抗体反应受到抑制。在分子水平上，我们发现BRD4在原发性GC B细胞分化和B细胞淋巴瘤中的作用是通过NF-κBp65磷酸化和易位受损以及B细胞淋巴瘤6（Bcl6）表达的进一步下调介导的。因此，本研究揭示了BRD4在控制GC B细胞发育途径中的新功能。
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Oncogene. 2017-3-2
Front Immunol. 2015-9-11
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