Negative regulation of CD40-mediated B cell responses by E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-B.

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Antigens, CD40, B-Lymphocytes, CD40 Ligand, Cell Proliferation, Cells, Cultured, Down-Regulation, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Knockout, Mitogen-Activated Protein Kinases, NF-kappa B, Protein Binding, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-cbl, TNF Receptor-Associated Factor 2, Ubiquitin
J. Immunol.
Date: Oct. 01, 2007
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