Cutting edge: CD40 engagement eliminates the need for Bruton's tyrosine kinase in B cell receptor signaling for NF-kappa B.
The Tec kinase Bruton's tyrosine kinase (Btk) represents a key intermediary for B cell receptor (BCR) signaling. Btk mutation produces B cell deficiency in mice with X-linked immunodeficiency (xid), and surface Ig-mediated responses of mature B cells are seriously deranged. The central role that Btk plays in directing downstream events produced by BCR engagement is demonstrated by the complete failure of NF-kappa B induction and cellular proliferation following anti-Ig treatment of B cells obtained from xid mice. In this study, we report that the block in BCR signaling produced by Btk mutation is reversed by CD40 engagement. Prior treatment with CD40 ligand normalized subsequent responses of xid B cells to BCR cross-linking, so that typical outcomes of BCR signaling such as NF-kappa B activation and cell cycle progression occurred in a Btk-independent fashion. These results demonstrate that a specific genetic lesion interrupting BCR-mediated intracellular signaling is circumvented through stimulation of CD40.
Mizuno
Takuya
T
Department of Medicine, School of Medicine and Immunobiology Unit, Evans Memorial Department of Clinical Research, Medical Center, Boston University, MA 02118, USA.
Rothstein
Thomas L
TL
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D023201:CD40 Ligand / Q000502:physiology*; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D008040:Genetic Linkage / Q000276:immunology; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007075:Immunoglobulin M / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014960:X Chromosome / Q000235:genetics / Q000276:immunology
D000888:Antibodies, Anti-Idiotypic; D019013:CD40 Antigens; D020672:I-kappa B Proteins; D007075:Immunoglobulin M; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM; D000072000:NF-KappaB Inhibitor alpha; D023201:CD40 Ligand; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse