Abstract
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-gamma2 (PLC-gamma2), 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Antibodies / immunology
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Antigens / immunology
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B-Lymphocytes / cytology
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B-Lymphocytes / enzymology*
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B-Lymphocytes / immunology*
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Cell Differentiation
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Cells, Cultured
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Down-Regulation
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Immune Tolerance / immunology*
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Immunoglobulins / immunology
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Immunoglobulins / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism
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Lupus Erythematosus, Systemic / enzymology
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology
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Lupus Erythematosus, Systemic / pathology
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Mice
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Mice, Knockout
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Protein Binding
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-cbl / deficiency
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism*
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Signal Transduction
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Syk Kinase
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Ubiquitin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies
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Antigens
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Cblb protein, mouse
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Immunoglobulins
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Intracellular Signaling Peptides and Proteins
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Ubiquitin
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Proto-Oncogene Proteins c-cbl
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Protein-Tyrosine Kinases
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Syk Kinase
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Syk protein, mouse
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Cbl protein, mouse