Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development
| Autor: | Laura Bergamaschi, Benjamin J. Stewart, Maxine G. B. Tran, Rachael Bashford-Rogers, Thomas M. Connor, Marion Espéli, Natalie Burrows, Girolamo Giudice, Richard J. Cornall, Paul A. Lyons, Ana Peñalver, Samuel L. Smith, Joscelin E. G. Smith, Kenneth G. C. Smith, Patrick H. Maxwell, Brian J. P. Huntly, Akimichi Inaba, John R. Ferdinand, Mukta Deobagkar-Lele, Evangelia Petsalaki, Menna R. Clatworthy, Vijesh J. Bhute |
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| Přispěvatelé: | Burrows, Natalie [0000-0001-6591-5971], Bashford-Rogers, Rachael JM [0000-0002-6838-0711], Stewart, Benjamin J [0000-0003-4522-0085], Smith, Joscelin EG [0000-0001-9271-1157], Deobagkar-Lele, Mukta [0000-0002-8543-6801], Petsalaki, Evangelia [0000-0002-8294-2995], Lyons, Paul A [0000-0001-7035-8997], Huntly, Brian JP [0000-0003-0312-161X], Maxwell, Patrick H [0000-0002-0338-2679], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Transcriptional Activation Lymphocyte Immunology B-cell receptor B-Lymphocyte Subsets Receptors Antigen B-Cell Biology Article CD19 Immunophenotyping 03 medical and health sciences Mice 0302 clinical medicine medicine Immunology and Allergy Animals Humans Lymphopoiesis B cell Mice Knockout B-Lymphocytes Acquired immune system Hypoxia-Inducible Factor 1 alpha Subunit 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure Hypoxia-inducible factors Gene Expression Regulation biology.protein Immunoglobulin Light Chains Bone marrow RNA Editing Biomarkers 030215 immunology Signal Transduction |
| Zdroj: | Nat Immunol |
| ISSN: | 1529-2916 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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