Abstract
Abstract CD40 is a TNF receptor (TNFR) superfamily member which is essential for B cell function. Cbl-b, an adapter protein and ubiquitin ligase, has been shown to regulate activation of T and B cells through their antigen receptors. In this study, we report that CD40-induced proliferation is significantly augmented in mice lacking Cbl-b. Furthermore, Cbl-b−/− mice display enhanced thymus–dependent (TD) Ab responses and germinal center (GC) formation, whereas introduction of CD40 deficiency abolishes the hyper-Ab responses and heightened GC formation in response to TD Ag challenge. Mechanistically, Cbl-b selectively down-modulates CD40-induced activation of NF-κB and JNK. Cbl-b associates with TNFR-associated factor 2 (TRAF-2) upon CD40 ligation, and inhibits the recruitment of TRAF-2 to the CD40. Together, our data suggest that Cbl-b attenuates CD40-mediated NF-κB and JNK activation, thereby suppressing B cell responses.
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