Work

BCR ligation selectively inhibits IgE class switch recombination 2258

Year: 2025

Type: article

Abstract: Description Mechanisms that restrict class switch recombination (CSR) to IgE limit subsequent IgE secretion and, therefore, the development of allergic disease. Mice with impaired B cell receptor (BCR) signaling have significantly increased IgE, indicating a role for BCR signaling in limiting responses. While prior work focused on BCR signaling in IgE-expressing cells to explain these findings, BCR signaling can also inhibit CSR. Therefore, we investigated the possibility that IgE CSR might be particularly sensitive to inhibition by BCR signaling. We found that immunization of mice with high-affinity antigen resulted in reduced IgE-expressing germinal center B cells and plasma cells compared to immunization with a low-affinity antigen. Mechanistic experiments with cultured mouse B cells demonstrated that BCR ligands selectively inhibited IgE CSR in a dose-, affinity-, and avidity-dependent manner. Signaling via Syk was required for the inhibition of IgE CSR following BCR stimulation, whereas inhibition of the PI3K subunit p110δ increased IgE CSR independently of BCR ligation. The inhibition of IgE CSR by BCR ligands synergized with IL-21 or TGFβ1. BCR ligation also inhibited CSR to IgE in human tonsillar B cells, and this inhibition was also synergistic with IL-21. These findings establish that IgE CSR is uniquely susceptible to inhibition by BCR signaling in mouse and human B cells, with important implications for the regulation and pathogenesis of allergic disease. Funding Sources Supported by: NIAID Award Number R01AI130470; Program for Breakthrough Biomedical Research, which is partially funded by the Sandler Foundation; the Sandler Asthma Basic Research Center; and the Cardiovascular Research Institute at UCSF; Doctoral Foreign Study Award from CIHR, award number DFD-170769; Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.196