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Dynamic regulation of hypoxia-inducible factor-1 alpha activity is essential for normal B cell development

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. Green open access

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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.

Type: Article
Title: Dynamic regulation of hypoxia-inducible factor-1 alpha activity is essential for normal B cell development
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41590-020-0772-8
Publisher version: https://doi.org/10.1038/s41590-020-0772-8
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Adaptive immunity, Clonal selection
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
URI: https://discovery.ucl.ac.uk/id/eprint/10112382
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