Hypoxia and hypoxia-inducible factor signals regulate the development, metabolism, and function of B cells

Abstract

Hypoxia is a common hallmark of healthy tissues in physiological states or chronically inflamed tissues in pathological states. Mammalian cells sense and adapt to hypoxia mainly through hypoxia-inducible factor (HIF) signaling. Many studies have shown that hypoxia and HIF signaling play an important regulatory role in development and function of innate immune cells and T cells, but their role in B cell biology is still controversial. B cells experience a complex life cycle (including hematopoietic stem cells, pro-B cells, pre-B cells, immature B cells, mature naïve B cells, activated B cells, plasma cells, and memory B cells), and the partial pressure of oxygen (PO₂) in the corresponding developmental niche of stage-specific B cells is highly dynamic, which suggests that hypoxia and HIF signaling may play an indispensable role in B cell biology. Based on the fact that hypoxia niches exist in the B cell life cycle, this review focuses on recent discoveries about how hypoxia and HIF signaling regulate the development, metabolism, and function of B cells, to facilitate a deep understanding of the role of hypoxia in B cell-mediated adaptive immunity and to provide novel strategies for vaccine adjuvant research and the treatment of immunity-related or infectious diseases.

Keywords: B cell biology; development; function; hypoxia; hypoxia-inducible factor signaling; metabolism.

Figure 1

B cell life cycle. In the BM, HSCs commit to the B cell lineage producing pro-B cells. Pro-B cells undergo VDJ recombination at the Ig heavy-chain locus to differentiate into pre-B cells, which rearrange Ig light-chain genes to further develop into IgM⁺ immature B cells. Immature B cells egress from the BM and migrate into peripheral lymphoid tissues via the circulation (transitional B cells) to complete maturation. Mature naïve B cells respond to Td antigens and develop into short-lived plasmablasts that secrete low-affinity antibodies. Activated B cells extensively proliferate with the help of Tfh cells in the GC of periphery lymphoid tissues (such as spleen, lymph node and Peyer’s patches), where B cells undergo SHM and CSR. Finally, B cells differentiate into high-affinity antibody-secreting plasma cells and long-lived memory B cells to provide specific and long-term protection for the body.

Figure 2

Regulation of HIF signaling in metazoan cells. HIFs are a kind of heterodimeric transcription factors that comprise an α subunit (O₂-sensitive) and a β subunit (constitutive). Under normoxia, proline residues in the ODD of HIF-α are hydroxylated by PHDs or FIH, which facilitates HIF-α binding to the VHL E3 ubiquitin ligase complex, and leads to polyubiquitination and proteosomal degradation. Hypoxia induces HIF-α protein stabilization by inactivating PHD and FIH. Activated HIF-α translocates from the cytoplasm to the nucleus, where it dimerizes with HIF-1β and recruits CBP/p300, and then binds to HRE (5’-RCGTG-3’) in the promoter or enhancer of HIF-regulated genes [including PCGs, hypoxia-responsive lncRNAs (HRLs) and hypoxamiRs], finally regulate a variety of hypoxia-adaptive pathways such as angiogenesis, anaerobic metabolism, and erythropoiesis.