B lymphocyte development and selection are central to adaptive immunity and self-tolerance. These processes require B cell receptor (BCR) signaling and occur in bone marrow, an environment with variable hypoxia, but whether hypoxia-inducible factor (HIF) is involved is unknown. We show that HIF activity is high in human and murine bone marrow pro-B and pre-B cells and decreases at the immature B cell stage. This stage-specific HIF suppression is required for normal B cell development because genetic activation of HIF-1α in murine B cells led to reduced repertoire diversity, decreased BCR editing and developmental arrest of immature B cells, resulting in reduced peripheral B cell numbers. HIF-1α activation lowered surface BCR, CD19 and B cell–activating factor receptor and increased expression of proapoptotic BIM. BIM deletion rescued the developmental block. Administration of a HIF activator in clinical use markedly reduced bone marrow and transitional B cells, which has therapeutic implications. Together, our work demonstrates that dynamic regulation of HIF-1α is essential for normal B cell development.

B 淋巴细胞的发育和选择对于适应性免疫和自我耐受至关重要。这些过程需要 B 细胞受体 (BCR) 信号传导，并发生在骨髓中，这是一种不同程度缺氧的环境，但缺氧诱导因子 (HIF) 是否参与尚不清楚。我们发现，HIF 活性在人和小鼠骨髓 pro-B 和 pre-B 细胞中较高，而在未成熟 B 细胞阶段则降低。这种阶段特异性 HIF 抑制是正常 B 细胞发育所必需的，因为小鼠 B 细胞中 HIF-1α 的基因激活会导致库多样性减少、BCR 编辑减少和未成熟 B 细胞发育停滞，从而导致外周 B 细胞数量减少。 HIF-1α 激活降低了表面 BCR、CD19 和 B 细胞激活因子受体，并增加了促凋亡 BIM 的表达。删除 BIM 挽救了开发障碍。临床使用 HIF 激活剂可显着减少骨髓和移行 B 细胞，这具有治疗意义。总之，我们的工作表明 HIF-1α 的动态调节对于正常 B 细胞发育至关重要。