Some people rely on the roll of a dice or the toss of a coin to make decisions. But, how does an immature, transitional B cell in the spleen decide whether to develop into a follicular B cell or a marginal-zone (MZ) B cell? Reporting in Nature Immunology, Tanigaki and colleagues now show that Notch–RBP-J signalling is required for this cell-fate decision.
Notch signalling, of which the DNA-binding protein RBP-J is a key mediator, regulates cell-fate decisions in various lineages. RBP-J deficiency results in embryonic lethality in mice, thereby precluding the study of B-cell development in these animals. Here, the authors used conditional mutagenesis to generate mice that selectively lacked B-cell expression of RBP-J (RBP-Jf/f × Cre mice), so that they could investigate the function of Notch–RBP-J in B-cell differentiation.
Anti-CD21 and anti-CD23 antibodies were used to discriminate between immature B cells, follicular B cells and MZ B cells in the spleens of RBP-Jf/f × Cre mice. Flow-cytometric analysis showed that MZ B cells were absent in these mice. Higher numbers of follicular B cells were observed in RBP-Jf/f × Cre mice compared with wildtype mice, which indicates that Notch–RBP-J signalling might normally act to promote MZ B-cell fate at the expense of follicular B-cell fate. RBP-J deficiency caused no defects in B-cell maintenance, survival or activation, or plasma-cell differentiation.
The lack of MZ B cells in the RBP-Jf/f × Cre mice might indicate a role for RBP-J in the maintenance of these cells, rather than a role in lineage commitment. To address this, the authors crossed the RBP-Jf/f mice with mice that carry the Cre transgene under the control of an interferon-inducible promoter, and they induced the deletion of RBP-J in adult mice. If RBP-J is required for the specific localization or survival of MZ B cells, then inducible deletion of RBP-J would result in the rapid disappearance of MZ B cells. If, however, RBP-J is required for the lineage commitment of MZ B cells, then the MZ B cells with the deleted allele would remain in their original location and gradually decrease in number with their natural lifespan. Induced deletion of RBP-J in adult mice caused a slow reduction in the number of MZ B cells, which confirms that RBP-J signalling is required to regulate a cell-fate decision between follicular and MZ B cells.
Does the loss of MZ B cells in the RBP-Jf/f × Cre mice affect their immune responses? Tanigaki and colleagues immunized these mice with Ficoll, lipopolysaccharide or chicken γ-globulin, and showed that the antibody responses to these antigens were normal. By contrast, these mice were more susceptible to infection with intravenously administered Staphylococcus aureus, which indicates that MZ B cells are important for the clearance of blood-borne bacterial infections.
As well as providing useful insights into the molecular mechanisms of MZ B-cell differentiation and function, the RBP-Jf/f mice will be important for future studies of Notch signalling in other tissues.
References
ORIGINAL RESEARCH PAPER
Tanigaki, T. et al. Notch–RBP-J signaling is involved in cell-fate determination of marginal-zone B cells. Nature Immunol. 3, 443–450 (2002)
FURTHER READING
Martin, F. & Kearney, J. F. Marginal-zone B cells. Nature Rev. Immunol. 2, 323–335 (2002)
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Buckland, J. Heads or tails?. Nat Rev Immunol 2, 307 (2002). https://doi.org/10.1038/nri816
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DOI: https://doi.org/10.1038/nri816