Csk restrains BCR-mediated ROS production and contributes to germinal center selection and affinity maturation.

IF 12.6 1区医学 Q1 IMMUNOLOGY

Journal of Experimental Medicine Pub Date : 2024-07-01 Epub Date: 2024-05-16 DOI:10.1084/jem.20231996

Takeshi Inoue, Yuma Matsumoto, Chie Kawai, Mao Ito, Shigeyuki Nada, Masato Okada, Tomohiro Kurosaki

引用次数: 0

Abstract

Compared with naïve B cells, the B cell receptor (BCR) signal in germinal center (GC) B cells is attenuated; however, the significance of this signaling attenuation has not been well defined. Here, to investigate the role of attenuation of BCR signaling, we employed a Csk mutant mouse model in which Csk deficiency in GC B cells resulted in augmentation of net BCR signaling with no apparent effect on antigen presentation. We found that Csk is required for GC maintenance and efficient antibody affinity maturation. Mechanistically, ROS-induced apoptosis was exacerbated concomitantly with mitochondrial dysfunction in Csk-deficient GC B cells. Hence, our data suggest that attenuation of the BCR signal restrains hyper-ROS production, thereby protecting GC B cells from apoptosis and contributing to efficient affinity maturation.

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Csk 可抑制 BCR 介导的 ROS 生成，并有助于生殖中心的选择和亲和性成熟。

与幼稚B细胞相比，生殖中心（GC）B细胞的B细胞受体（BCR）信号减弱；然而，这种信号减弱的意义尚未得到很好的界定。在这里，为了研究 BCR 信号衰减的作用，我们采用了 Csk 突变小鼠模型，在该模型中，GC B 细胞中 Csk 的缺乏会导致 BCR 净信号增强，但对抗原递呈无明显影响。我们发现，Csk 是维持 GC 和高效抗体亲和力成熟所必需的。从机理上讲，在 Csk 缺乏的 GC B 细胞中，ROS 诱导的细胞凋亡与线粒体功能障碍同时加剧。因此，我们的数据表明，减弱 BCR 信号可抑制高 ROS 的产生，从而保护 GC B 细胞免于凋亡并促进有效的亲和力成熟。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Experimental Medicine 医学-免疫学

CiteScore

26.60

自引率

1.30%

发文量

189

审稿时长

3-8 weeks

期刊介绍： Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.