Research Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.
J Exp Med. 2012 Apr 9;209(4):775-92. doi: 10.1084/jem.20112422. Epub 2012 Apr 2.
The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, pro-B cell development, and subsequent transition to the pre-B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient FO B cells. Immune responses were severely reduced upon Ebf1 inactivation, as GCs were formed but not maintained. ChIP- and RNA-sequencing of FO B cells identified EBF1-activated genes that encode receptors, signal transducers, and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity.
转录因子 EBF1 是早期 B 细胞发育中谱系特化所必需的。在这项研究中，我们通过条件性突变证明 EBF1 对于 B 细胞的定型、前 B 细胞的发育以及随后向 pre-B 细胞阶段的过渡是必需的。在 B 细胞发育的后期，EBF1 对于几种成熟 B 细胞类型的产生和维持是必需的。边缘区和 B-1 B 细胞缺失，而滤泡（FO）和生发中心（GC）B 细胞则减少。在没有 EBF1 的情况下，B 细胞受体的激活导致 FO B 细胞的细胞内信号转导、增殖和存活受损。EBF1 失活后，免疫反应严重降低，因为 GC 形成但不能维持。FO B 细胞的 ChIP-seq 和 RNA-seq 鉴定了 EBF1 激活的基因，这些基因编码的受体、信号转导物和转录因子参与了 B 细胞信号转导。值得注意的是，EBF1 的异位表达有效地诱导了 B-1 细胞的发育，而牺牲了常规 B 细胞。这些功能获得和缺失分析揭示了 EBF1 在控制 B 细胞免疫中的新的重要功能。
