B-lymphocyte development and selection is 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 high HIF-activity in human bone marrow pro/preB cells that decreased at the immature B cell stage. Stage-specific HIF-suppression was required for B cell development, since constitutive HIF-1α-activation in murine B cells led to immature B cell developmental-arrest, limited BCR-editing and reduced repertoire-diversity. Disruption of HIF-1α-regulation reduced surface BCR and CD19 and increased expression of pro-apoptotic BIM. Transient administration of a clinical HIF-activator reduced immature and transitional B cells, confirming the on-going importance of this axis for the maintenance of the established B cell-compartment. Our work identifies a critical role for HIF-1α in tuning BCR-signal strength and demonstrates that dynamic HIF-regulation is essential for normal B cell development, with significant clinical implications.
Keywords: Hypoxia-inducible factor, B cell development, B cell repertoire, central-tolerance, selection, lymphopenia
Burrows, Natalie and Bashford-Rogers, Rachael J.M. and Bhute, Vijesh J. and Penalver, Ana and Ferdinand, John R. and Stewart, Benjamin J. and Smith, Joscelin E.G. and Deobagkar-Lele, Mukta and Giudice, Girolamo and Connor, Thomas M. and Inaba, Akimichi and Bergamaschi, Laura and Smith, Sam and Tran, Maxine G.B. and Petsalaki, Evangelia and Lyons, Paul A. and Espeli, Marion and Smith, Kenneth G.C. and Cornall, Richard J. and Clatworthy, Menna R. and Maxwell, Patrick H., Dynamic Regulation of HIF Activity is Essential for Normal B Cell Development (June 14, 2019). Available at SSRN: https://ssrn.com/abstract=3404262 or http://dx.doi.org/10.2139/ssrn.3404262
This version of the paper has not been formally peer reviewed.
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