Modulation of B cell activation threshold mediated by BCR/CD40 costimulation by targeting Cbl-b for ubiquitination |
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| Authors: | Na Tang Lifen Yang Dongdong Li Rushi Liu Jian Zhang |
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| Institution: | 1. Laboratory of Medical Molecular and Immunological Diagnostics (LMMID), Hunan Normal University, 371 Tongzipo Road, Changsha, Hunan, 410013, PR China;2. Department of Pediatrics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, PR China;3. Department of Orthopedics, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL, 60612, USA;4. Section of Nephrology, Department of Medicine, University of Chicago, 5841 South Maryland Ave., Chicago, IL, 60637, USA;5. Department of Pathology, University of Iowa, 25 S. Grand Ave., Iowa City, IA, 52242, USA |
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| Abstract: | It has been shown that CD40 is required for optimal B cell activation. Casitas-B-lineage lymphoma-b (Cbl-b), a RING finger E3 ubiquitin ligase, inhibits B cell activation. In this report, we demonstrate that CD40 stimulation markedly enhances IgM-induced B cell proliferation in wild-type (WT) mice, whereas this cell proliferation was reduced in CD40-deficient (Cd40?/?) mice. Interestingly, CD40 ligation strongly augments IgM-induced Cbl-b ubiquitination and degradation in primary mouse B cells, which closely correlates with their proliferation capacity. Cbl-b deficiency uncouples BCR-induced B cell proliferation from CD40 costimulation. Our results indicate that Cbl-b negatively regulates costimulation of BCR and CD40, possibly by setting the threshold for B cell activation via controlling Cbl-b expression. |
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