Immune Receptor Activation Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Immune Receptor Activation Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London NW3 2PF, UK.
Immunity. 2021 Dec 14;54(12):2756-2771.e10. doi: 10.1016/j.immuni.2021.11.006. Epub 2021 Dec 7.
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.
与其他抗体同种型不同，转换为 IgE 的 B 细胞会短暂响应，并且不会产生长寿的浆细胞 (PC) 或记忆 B 细胞。为了更好地理解 IgE-BCR 介导的 IgE 反应控制，我们开发了全基因组 CRISPR 筛选，使我们能够比较 IgE 和 IgG1 B 细胞增殖、存活和分化为 PC 的要求。IgE PC 表现出对 PI3K-mTOR 轴的依赖性，该依赖性增加了转录因子 IRF4 的蛋白量。相比之下，钙调神经磷酸酶-NFAT 途径的成分缺失促进了 IgE PC 的分化。表达 B 细胞特异性 calcineurin B1 缺失的小鼠表现出 IgE PC 产生增加。从机制上讲，IgE-BCR 下游的持续升高的细胞内钙促进了 BCL2L11 依赖性细胞凋亡。因此，IgE-BCR 下游的慢性钙信号控制 IgE 反应的自我限制特征，并且可能与过敏疾病中 IgE 产生细胞的积累有关。
