Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
Eur J Immunol. 2011 Aug;41(8):2404-13. doi: 10.1002/eji.201141553. Epub 2011 Jul 6.
The transcription factor Bcl6 regulates germinal center formation and differentiation of B cells into high-affinity antibody-producing plasma cells. The direct double-negative regulatory circuit between Bcl6 and Blimp-1 is well established. We now reveal alternative mechanisms for Bcl6-mediated regulation of B-cell differentiation to plasma cells and show with DT40 cells that Bcl6 directly promotes the expression of Bach2, a known suppressor of Blimp-1. Moreover, Bcl6 suppresses Blimp-1 expression through direct binding to the IRF4 gene, as well as by promoting the expression of MITF, a known suppressor of IRF4. We also provide evidence that Bcl6 is needed for the expression of AID and UNG, the indispensable proteins for somatic hypermutation and class-switch recombination, and UNG appears to be a direct Bcl6 target. Our findings reveal a complex regulatory network in which Bcl6 acts as a key element dictating the transition of DT40 B cells to plasma cells.
转录因子 Bcl6 调节生发中心的形成和 B 细胞向高亲和力产生抗体的浆细胞的分化。Bcl6 和 Blimp-1 之间的直接双阴性调节回路已经得到很好的建立。我们现在揭示了 Bcl6 介导的 B 细胞向浆细胞分化的调节的替代机制，并通过 DT40 细胞表明，Bcl6 直接促进 Bach2 的表达，Bach2 是 Blimp-1 的已知抑制剂。此外，Bcl6 通过直接结合 IRF4 基因以及促进 MITF 的表达来抑制 Blimp-1 的表达，MITF 是 IRF4 的已知抑制剂。我们还提供了证据表明，Bcl6 对于 AID 和 UNG 的表达是必需的，AID 和 UNG 是体细胞超突变和类别转换重组所必需的蛋白质，UNG 似乎是 Bcl6 的直接靶标。我们的发现揭示了一个复杂的调控网络，其中 Bcl6 作为决定 DT40 B 细胞向浆细胞转化的关键因素发挥作用。
