Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development.
Burrows N., Bashford-Rogers RJM., Bhute VJ., Peñalver A., Ferdinand JR., Stewart BJ., Smith JEG., Deobagkar-Lele M., Giudice G., Connor TM., Inaba A., Bergamaschi L., Smith S., Tran MGB., Petsalaki E., Lyons PA., Espeli M., Huntly BJP., Smith KGC., Cornall RJ., Clatworthy MR., Maxwell PH.
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.