生发中心
B细胞
生物
B细胞受体
抗体
记忆B细胞
免疫球蛋白类转换
断点群集区域
幼稚B细胞
免疫球蛋白G
转录因子
受体
分子生物学
细胞生物学
免疫学
免疫系统
T细胞
遗传学
抗原提呈细胞
基因
作者
Lingling Zhang,Amparo Toboso-Navasa,Arief Gunawan,Abdouramane Camara,Rinako Nakagawa,Katja Finsterbusch,Probir Chakravarty,Rebecca Newman,Zaixing Yang,Martin Eilers,Andreas Wack,Pavel Tolar,Kai‐Michael Toellner,Dinis Pedro Calado
出处
期刊:Science immunology
[American Association for the Advancement of Science (AAAS)]
日期:2024-04-05
卷期号:9 (94)
标识
DOI:10.1126/sciimmunol.adk0092
摘要
The transition from immunoglobulin M (IgM) to affinity-matured IgG antibodies is vital for effective humoral immunity. This is facilitated by germinal centers (GCs) through affinity maturation and preferential maintenance of IgG + B cells over IgM + B cells. However, it is not known whether the positive selection of the different Ig isotypes within GCs is dependent on specific transcriptional mechanisms. Here, we explored IgG1 + GC B cell transcription factor dependency using a CRISPR-Cas9 screen and conditional mouse genetics. We found that MIZ1 was specifically required for IgG1 + GC B cell survival during positive selection, whereas IgM + GC B cells were largely independent. Mechanistically, MIZ1 induced TMBIM4, an ancestral anti-apoptotic protein that regulated inositol trisphosphate receptor (IP3R)–mediated calcium (Ca 2+ ) mobilization downstream of B cell receptor (BCR) signaling in IgG1 + B cells. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction–induced IgG1 + GC cell death caused by excessive Ca 2+ accumulation. This study uncovers a unique Ig isotype–specific dependency on a hitherto unidentified mechanism in GC-positive selection.
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