Negative regulation of CD40-mediated B cell responses by E3 ubiquitin ligase casitas-B-lineage lymphoma protein-B
Negative regulation of CD40-mediated B cell responses by E3 ubiquitin ligase casitas-B-lineage lymphoma protein-B
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DOI：
10.4049/jimmunol.179.7.4473
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发表时间：
2007-10-01
影响因子：
4.4
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Qiao, Guilin;Lei, Minxiang;Zhang, Jian
已有文献证明CD40是B细胞功能所必需的。酪蛋白-B细胞系淋巴瘤蛋白-b(Cbl-b)是一种连接蛋白和泛素连接酶，通过其Ag受体调节T和B细胞的激活。在这项研究中，我们报告CD40诱导的B细胞增殖在缺乏Cbl-b的小鼠中显著增强。此外，Cbl-b(-/-)小鼠表现出增强的胸腺依赖性抗体反应和生发中心形成，而CD40缺陷的引入消除了这些影响。Cbl-b(-/-)小鼠过度依赖胸腺的不道德反应部分是由于B细胞的固有缺陷。在机制上，Cbl-b选择性地下调CD40诱导的核因子-kappaB和JNK的激活。CBL-b在CD40连接时与肿瘤坏死因子受体相关因子2结合，并抑制肿瘤坏死因子受体相关因子2向CD40的募集。总之，我们的数据表明，Cbl-b减弱了CD40介导的NF-kappa B和JNK的激活，从而抑制了B细胞的反应。
It has been documented that CD40 is essential for B cell function. Casitas-B-lineage lymphoma protein-b (Cbl-b), an adapter protein and ubiquitin ligase, has been shown to regulate the activation of T and B cells through their Ag receptors. In this study, we report that CD40-induced B cell proliferation is significantly augmented in mice lacking Cbl-b. Furthermore, Cbl-b(-/-) mice display enhanced thymus-dependent Ab responses and germinal center formation, whereas introduction of CD40 deficiency abolishes these effects. Hyper thymus-dependent Immoral response in Cbl-b(-/-) mice is in part due to an intrinsic defect in B cells. Mechanistically, Cbl-b selectively down-modulates CD40-induced activation of NF-kappa B and JNK. Cbl-b associates with TNF receptor-associated factor 2 upon CD40 ligation, and inhibits the recruitment of TNF receptor-associated factor 2 to the CD40. Together, our data suggest that Cbl-b attenuates CD40-mediated NF-kappa B and JNK activation, thereby suppressing B cell responses.