Burrows, N;
Bashford-Rogers, RJM;
Bhute, VJ;
Penalver, A;
Ferdinand, JR;
Stewart, BJ;
Smith, JEG;
... Maxwell, PH; + view all
(2020)
Dynamic regulation of hypoxia-inducible factor-1 alpha activity is essential for normal B cell development.
Nature Immunology
, 21
pp. 1408-1420.
10.1038/s41590-020-0772-8.
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Abstract
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.
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