title: Transmodulation of BCR signaling by transduction-incompetent antigen receptors: implications for impaired signaling in anergic B cells.
abstract: B cell tolerance can be maintained by functional inactivation, or anergy, wherein B cell Ag receptors (BCR) remain capable of binding Ag, but are unable to transduce signals. Although the molecular mechanisms underlying this unresponsiveness are unknown, some models of B cell anergy are characterized by disruption of proximal BCR signaling events, and by destabilization of the BCR complex. Receptor destabilization is manifest by a reduced ability to coimmunoprecipitate membrane Ig with the Ig-alpha/Ig-beta signal-transducing complex. To begin to explore the possibility that anergy is the consequence of receptor destabilization, we analyzed a panel of B lymphoma transfectants expressing constant amounts of signal-competent Ag receptors and varied amounts of a receptor with identical specificity, but bearing mutations that render it incapable of interacting with Ig-alpha/Ig-beta. This analysis revealed that coaggregation of signal-incompetent receptors prevented Ag-induced Ig-alpha and Syk phosphorylation, mobilization of Ca(2+), and the up-regulation of CD69 mediated by competent receptors. In contrast, Ag-induced Cbl and Erk phosphorylation were unaffected. Data indicate that coaggregation of destabilized receptors (as few as approximately 15% of total) with signal-competent receptors significantly affects the ability of competent receptors to transduce signals. Thus, BCR destabilization may underlie the Ag unresponsiveness of anergic B cells.
authors.affiliation: Integrated Department of Immunology, University of Colorado Health Sciences Center, and National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Vilen
authors.forename: Kathy M
authors.initials: KM
authors.lastname: Burke
authors.forename: Michelle
authors.initials: M
authors.lastname: Sleater
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology*; D051925:CD79 Antigens; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D017635:Clonal Anergy; D004792:Enzyme Precursors / Q000378:metabolism; D007072:Immunoglobulin D / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D016393:Lymphoma, B-Cell; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D011940:Receptor Aggregation; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D000099192:CD69 Antigens
chemical_list: D000941:Antigens; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051925:CD79 Antigens; D002118:Calcium; D004792:Enzyme Precursors; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D020928:Mitogen-Activated Protein Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D011947:Receptors, Antigen, B-Cell; D000072377:Syk Kinase; D044767:Ubiquitin-Protein Ligases; D000099192:CD69 Antigens; C000606896:SYK protein, human; C067419:CBL protein, human