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

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.

journal_name

Nat Immunol

journal_title

Nature immunology

authors

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,Corn

doi

10.1038/s41590-020-0772-8

subject

Has Abstract

pub_date

2020-11-01 00:00:00

pages

1408-1420

issue

11

eissn

1529-2908

issn

1529-2916

pii

10.1038/s41590-020-0772-8

journal_volume

21

pub_type

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