Abstract
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 aB 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.
Highlights
Bcells play crucial roles in immunity by recognizing foreign antigens and eliciting protective responses
Genome-wide CRISPR screens in primary B lymphocytes To evaluate the efficiency of CRISPR-mediated gene editing in primary B cells, we transduced B cells expressing Cas9-GFP (Platt et al, 2014) with mCherry-expressing constructs containing single guide RNAs targeting the surface receptor CD22
To test targeting efficiency in vivo, we generated chimeras by adoptive transfer of GFP-Cas9-expressing hematopoietic stem cells (HSCs), which were lentivirally transduced with Cd22 targeting single guide RNAs (sgRNAs), into lethally irradiated B6.SJL.CD45.1 congenic mice (Figure S1C)
Summary
Bcells play crucial roles in immunity by recognizing foreign antigens and eliciting protective responses. The IgE-BCR differs from IgM- and IgG1-BCRs in that it initiates signaling in the absence of antigen, limiting B cell proliferation and stimulating precocious differentiation into IgE+ plasma cells (PCs) (Haniuda et al, 2016; Yang et al, 2012). This mirrors the low and transient IgE+ B cell numbers, their differentiation into short-lived PCs, and the lack of IgE memory B cells in vivo (Erazo et al, 2007; He et al, 2013; Yang et al, 2012), arguing that signaling from the IgE-BCR critically regulates IgE production
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