Department of Molecular Pathology, Institute of Pathology, University of Würzburg, Josef Schneider-Str. 2, 97080, Würzburg, Germany.
Institute of Translational and Stratified Medicine, Faculty of Medicine and Dentistry, University of Plymouth, Plymouth, PL6 8BU, UK.
Cell Mol Immunol. 2019 May;16(5):508-520. doi: 10.1038/s41423-018-0052-9. Epub 2018 Jun 15.
B cell development in bone marrow is a precisely regulated complex process. Through successive stages of differentiation, which are regulated by a multitude of signaling pathways and an array of lineage-specific transcription factors, the common lymphoid progenitors ultimately give rise to mature B cells. Similar to early thymocyte development in the thymus, early B cell development in bone marrow is critically dependent on IL-7 signaling. During this IL-7-dependent stage of differentiation, several transcription factors, such as E2A, EBF1, and Pax5, among others, play indispensable roles in B lineage specification and maintenance. Although recent studies have implicated several other transcription factors in B cell development, the role of NFATc1 in early B cell developmental stages is not known. Here, using multiple gene-manipulated mouse models and applying various experimental methods, we show that NFATc1 activity is vital for early B cell differentiation. Lack of NFATc1 activity in pro-B cells suppresses EBF1 expression, impairs immunoglobulin gene rearrangement, and thereby preBCR formation, resulting in defective B cell development. Overall, deficiency in NFATc1 activity arrested the pro-B cell transition to the pre-B cell stage, leading to severe B cell lymphopenia. Our findings suggest that, along with other transcription factors, NFATc1 is a critical component of the signaling mechanism that facilitates early B cell differentiation.
骨髓中的 B 细胞发育是一个精确调控的复杂过程。通过一系列受多种信号通路和一系列谱系特异性转录因子调控的分化阶段，共同淋巴样祖细胞最终产生成熟的 B 细胞。类似于胸腺中早期 T 细胞的发育，骨髓中早期 B 细胞的发育严重依赖于 IL-7 信号。在这个依赖于 IL-7 的分化阶段，几个转录因子，如 E2A、EBF1 和 Pax5 等，在 B 细胞谱系的特异性和维持中发挥不可或缺的作用。尽管最近的研究表明其他几个转录因子也参与了 B 细胞的发育，但 NFATc1 在早期 B 细胞发育阶段的作用尚不清楚。在这里，我们使用多种基因操作的小鼠模型和应用各种实验方法，表明 NFATc1 活性对于早期 B 细胞分化至关重要。在 pro-B 细胞中缺乏 NFATc1 活性会抑制 EBF1 的表达，损害免疫球蛋白基因重排，从而影响 preBCR 的形成，导致 B 细胞发育缺陷。总的来说，NFATc1 活性的缺乏阻止了 pro-B 细胞向 pre-B 细胞阶段的过渡，导致严重的 B 细胞淋巴细胞减少症。我们的研究结果表明，与其他转录因子一起，NFATc1 是促进早期 B 细胞分化的信号机制的关键组成部分。
