Qiao Guilin, Lei Minxiang, Li Zhenping, Sun Yonglian, Minto Andrew, Fu Yang-Xin, Ying Haiyan, Quigg Richard J, Zhang Jian
Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL 6063, USA.
J Immunol. 2007 Oct 1;179(7):4473-9. doi: 10.4049/jimmunol.179.7.4473.
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 humoral 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-kappaB 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-kappaB and JNK activation, thereby suppressing B cell responses.
已有文献证明，CD40对B细胞功能至关重要。Casitas-B系淋巴瘤蛋白-b（Cbl-b）是一种衔接蛋白和泛素连接酶，已显示其可通过T细胞和B细胞的抗原受体调节T细胞和B细胞的激活。在本研究中，我们报告在缺乏Cbl-b的小鼠中，CD40诱导的B细胞增殖显著增强。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，而引入CD40缺陷则消除了这些效应。Cbl-b(-/-)小鼠中胸腺依赖性体液反应增强部分归因于B细胞的内在缺陷。从机制上讲，Cbl-b选择性下调CD40诱导的NF-κB和JNK激活。CD40连接后，Cbl-b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CD40介导的NF-κB和JNK激活，从而抑制B细胞反应。
