Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b.
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.
Kitaura
Yasuyuki
Y
Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Jang
Ihn Kyung
IK
Wang
Yan
Y
Han
Yoon-Chi
YC
Inazu
Tetsuya
T
Cadera
Emily J
EJ
Schlissel
Mark
M
Hardy
Richard R
RR
Gu
Hua
H
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D015536:Down-Regulation; D007108:Immune Tolerance / Q000276:immunology*; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D025801:Ubiquitin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D000941:Antigens; C118387:Cblb protein, mouse; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D025801:Ubiquitin; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C493849:Cbl protein, mouse