Chronic calcium signaling in IgE+ B cells limits plasma cell differentiation and survival

In contrast to other antibody isotypes, B cells switched to IgE respond transiently and do not give rise to long-lived plasma cells (PCs) or memory B cells. To better understand IgE-BCR-mediated control of IgE responses, we developed whole-genome CRISPR screening that enabled comparison of IgE(+) and IgG1(+) B cell requirements for proliferation, survival, and differentiation into PCs. IgE(+) PCs exhibited dependency on the PI3K-mTOR axis that increased protein amounts of the transcription factor IRF4. In contrast, loss of components of the calcium-calcineurin-NFAT pathway promoted IgE(+) PC differentiation. Mice bearing a B cell-specific deletion of calcineurin B1 exhibited increased production of IgE(+) PCs. Mechanistically, sustained elevation of intracellular calcium in IgE(+) PCs downstream of the IgE-BCR promoted BCL2L11-dependent apoptosis. Thus, chronic calcium signaling downstream of the IgE-BCR controls the self-limiting character of IgE responses and may be relevant to the accumulation of IgE-producing cells in allergic disease.

Automated summary

In contrast to other antibody isotypes, B cells switched to IgE respond transiently and do not give rise to long-lived plasma cells (PCs) or memory B cells. IgE(+) PCs exhibit dependency on the PI3K-mTOR axis that increases protein amounts of the transcription factor IRF4, while loss of components of the calcium-calcineurin-NFAT pathway promotes IgE(+) PC differentiation.