Immunity
Volume 26, Issue 5, 25 May 2007, Pages 567-578
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Article
Control of the B Cell-Intrinsic Tolerance Programs by Ubiquitin Ligases Cbl and Cbl-b

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Summary

B cell receptor (BCR) signaling plays a critical role in B cell tolerance and activation. Here, we show that mice with B cell-specific ablation of both Cbl and Cbl-b (Cbl−/−Cblb−/−) manifested systemic lupus erythematosus (SLE)-like autoimmune disease. The Cbl double deficiency resulted in a substantial increase in marginal zone (MZ) and B1 B cells. The mutant B cells were not hyperresponsive in terms of proliferation and antibody production upon BCR stimulation; however, B cell anergy to protein antigen appeared to be impaired. Concomitantly, BCR-proximal signaling, including tyrosine phosphorylation of Syk tyrosine kinase, Phospholipase C-γ2 (PLC-γ2), and Rho-family GTP-GDP exchange factor Vav, and Ca2+ mobilization were enhanced, whereas tyrosine phosphorylation of adaptor protein BLNK was substantially attenuated in the mutant B cells. These results suggested that the loss of coordination between these pathways was responsible for the impaired B cell tolerance induction. Thus, Cbl proteins control B cell-intrinsic checkpoint of immune tolerance, possibly through coordinating multiple BCR-proximal signaling pathways during anergy induction.

SIGNALING
MOLIMMUNO

Cited by (0)

5

Present address: RIKEN BioSource Center, Tsukuba-Shi, Ibaraki 305-0074, Japan.

6

Present address: The Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.

7

Present address: Department of Clinic Research, Saigata National Hospital, Joetsu, Niigata 949-3193, Japan.