VHL shapes the pre-immune B cell-repertoire by controlling HIF-1α

The development and selection of B-lymphocytes is central to adaptive immunity and self-tolerance. These processes occur in the bone marrow, an environment with variable hypoxia, but whether the Hypoxia-inducible factor (HIF) pathway contributes to shaping the developing B cell repertoire is unknown. We found that HIF-1 activation in the mouse B cell lineage led to immature B cell developmental arrest, reduced B cell repertoire diversity and peripheral B cell lymphopenia. HIF-1 limited receptor-editing and lowered the survival threshold of immature B cells by modulating BCR signal strength and the expression of pro-apoptotic protein BIM. Inactivation of one HIF-1 allele resulted in an intermediate phenotype, implying a tunable response. Acute administration of a HIF-activator in clinical use produced a similar phenotype. Our findings identify a critical role for HIF-1 in modulating the threshold for B cell selection and provide insight into how oxygen-sensing contributes to B cell development and central-tolerance.