| First Author | Burrows N | Year | 2020 |
| Journal | Nat Immunol | Volume | 21 |
| Issue | 11 | Pages | 1408-1420 |
| PubMed ID | 32868930 | Mgi Jnum | J:306374 |
| Mgi Id | MGI:6706636 | Doi | 10.1038/s41590-020-0772-8 |
| Citation | Burrows N, et al. (2020) Dynamic regulation of hypoxia-inducible factor-1alpha activity is essential for normal B cell development. Nat Immunol 21(11):1408-1420 |
| abstractText | 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-1alpha 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-1alpha 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-1alpha is essential for normal B cell development. |
