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Negative Regulation of CD40-Mediated B Cell Responses by E3 Ubiquitin Ligase Casitas-B-Lineage Lymphoma Protein-B¹

Guilin Qiao^2,*,, Minxiang Lei^2,*, Zhenping Li^*, Yonglian Sun^,, Andrew Minto^*, Yang-Xin Fu^,, Haiyan Ying^*,, Richard J. Quigg^* and Jian Zhang^3,*,

^* Sections of Nephrology, Department of Medicine, Department of Pathology, Committee on Immunology, University of Chicago, Chicago, IL 60637

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-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-B and JNK activation, thereby suppressing B cell responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The project described was supported by Grants K02 AR049047 and R01AR049775 (to J.Z.) from the National Institutes of Health, and Grants-in-aid (0355509Z and 0650181Z to J.Z.) from the American Heart Association.

² G.Q. and M.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Jian Zhang, Section of Nephrology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail address: jzhang{at}medicine.bsd.uchicago.edu

⁴ Abbreviations used in this paper: GC, germinal center; TD, thymus dependent; Cbl-b, Casitas-B-lineage lymphoma protein-b; PTK, protein tyrosine kinase; TKB, PTK binding; Ub, ubiquitin; TRAF-2, TNFR-associated factor 2; WT, wild type; PI, propidium iodide; TI, thymus independent; KLH, keyhole limpet hemocyanin.