School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Australia.
School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Australia; School of Molecular Sciences, Faculty of Science, The University of Western Australia, Australia.
Mol Immunol. 2020 Dec;128:150-164. doi: 10.1016/j.molimm.2020.10.001. Epub 2020 Oct 28.
During mammalian lymphoid development, Notch signaling is necessary at multiple stages of T lymphopoiesis, including lineage commitment, and later stages of T cell effector differentiation. In contrast, outside of a defined role in the development of splenic marginal zone B cells, there is conflicting evidence regarding whether Notch signaling plays functional roles in other B cell sub-populations. Complement receptor 2 (CR2) modulates BCR-signaling and is tightly regulated throughout differentiation. During B lymphopoiesis, CR2 is detected on immature and mature B cells with high surface expression on marginal zone B cells. Here, we have explored the possibility that Notch regulates human CR2 transcriptional activity using in vitro models including a co-culture system, co-transfection gene reporters and chromatin accessibility assays. We provide evidence that Notch signaling regulates CR2 promoter activity in a mature B cell line, as well as the induction of endogenous CR2 mRNA in a non-expressing pre-B cell line. The dynamics of endogenous gene activation suggests additional unidentified factors are required to mediate surface CR2 expression on immature and mature B lineage cells.
在哺乳动物的淋巴样发育过程中，Notch 信号在 T 淋巴样细胞的多个发育阶段都起着重要作用，包括谱系决定和 T 细胞效应分化的后期阶段。相比之下，除了在脾脏边缘区 B 细胞发育中的明确作用之外，关于 Notch 信号在其他 B 细胞亚群中是否发挥功能作用，还存在相互矛盾的证据。补体受体 2（CR2）调节 BCR 信号，并在分化过程中受到严格调控。在 B 淋巴样细胞发育过程中，CR2 可在不成熟和成熟 B 细胞上检测到，在边缘区 B 细胞上的表面表达水平较高。在这里，我们使用体外模型（包括共培养系统、共转染基因报告基因和染色质可及性测定）探索了 Notch 调节人类 CR2 转录活性的可能性。我们提供的证据表明，Notch 信号在成熟 B 细胞系中调节 CR2 启动子活性，以及在不表达的前 B 细胞系中诱导内源性 CR2 mRNA 的表达。内源性基因激活的动力学表明，还需要其他未鉴定的因子来介导不成熟和成熟 B 谱系细胞表面的 CR2 表达。
