Open AccessDynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development
Author(s) -
Natalie Burrows,
Rachael Bashford-Rogers,
Vijesh J. Bhute,
Ana Peñalver,
John R. Ferdinand,
Benjamin J Stewart,
Joscelin E. G. Smith,
Mukta Deobagkar-Lele,
Girolamo Giudice,
Thomas M. Connor,
Akimichi Inaba,
Laura Bergamaschi,
Sam Smith,
Maxine Tran,
Evangelia Petsalaki,
Paul Lyons,
Marion Espéli,
Brian J.P. Huntly,
Kenneth Smith,
Richard J. Cornall,
Menna R. Clatworthy,
Patrick H. Maxwell
Publication year - 2020
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-020-0772-8
Subject(s) - b cell , cd19 , biology , microbiology and biotechnology , bone marrow , hypoxia inducible factors , cell , immunology , cancer research , immune system , antibody , genetics , gene
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.