ABSTRACT
The proper regulation of IgE production safeguards against allergic disease, highlighting the importance of mechanisms that restrict IgE plasma cell (PC) survival. IgE PCs have unusually high surface B cell receptor (BCR) expression, yet the functional consequences of ligating this receptor are unknown. Here, we found that BCR ligation induced BCR signaling in IgE PCs followed by their elimination. In cell culture, exposure of IgE PCs to cognate antigen or anti-BCR antibodies induced apoptosis. IgE PC depletion correlated with the affinity, avidity, amount, and duration of antigen exposure and required the BCR signalosome components Syk, BLNK, and PLCγ2. In mice with a PC-specific impairment of BCR signaling, the abundance of IgE PCs was selectively increased. Conversely, BCR ligation by injection of cognate antigen or anti-IgE depleted IgE PCs. These findings establish a mechanism for the elimination of IgE PCs through BCR ligation. This has important implications for allergen tolerance and immunotherapy as well as anti-IgE monoclonal antibody treatments.
Competing Interest Statement
C.D.C.A. is a member of the scientific advisory board for Walking Fish Therapeutics. C.D.C.A.'s spouse is an employee and shareholder of Bristol Myers Squibb. Z.Y. is an employee of Genentech and a shareholder in the Roche Group. These companies had no involvement in this work. The authors have no other financial conflicts of interest to declare.
Footnotes
1. Figure 1 was revised and split into two figures (Figure 1 and S2) to provide additional quantification graphs and statistics. 2. A new Figure S1 was added to show a representative flow cytometry gating scheme. 3. Figure 6 and the associated supplementary figure were rearranged to new Figures 6 and 7. 4. New data was added showing that cognate antigen exposure in vivo results in a selective reduction in antigen-specific IgE PCs (Figure 7). 5. Modifications were made in the text to incorporate the changes above and clarify the relationship of the work to prior studies. 6. References and mouse nomenclature were updated.