title: Entry of B cell receptor into signaling domains is inhibited in tolerant B cells.
abstract: Signal transduction through the B cell antigen receptor (BCR) is altered in B cells that express a receptor that recognizes self-antigen. To understand the molecular basis for the change in signaling in autoreactive B cells, a transgenic model was used to isolate a homogeneous population of tolerant B lymphocytes. These cells were compared with a similar population of naive B lymphocytes. We show that the BCR from naive B cells enters a detergent-insoluble domain of the cell within 6 s after antigen binding, before a detectable increase in BCR phosphorylation. This fraction appears to be important for signaling because it is enriched for lyn kinase but lacks CD45 tyrosine phosphatase and because the BCR that moves into this domain becomes more highly phosphorylated. Partitioning of the BCR into this fraction is unaffected by src family kinase inhibition. Tolerant B cells do not efficiently partition the BCR into the detergent-insoluble domain, providing an explanation for their reduced tyrosine kinase activation and calcium flux in response to antigen. These results identify an early, regulated step in antigen receptor signaling and self-tolerance.
authors.affiliation: Australian Cancer Research Foundation Genetics Laboratory, Medical Genome Centre, John Curtin School of Medical Research, Canberra 2601, Australia.
authors.forename: B C
authors.initials: BC
authors.lastname: Weintraub
authors.forename: J E
authors.initials: JE
authors.lastname: Jun
authors.forename: A C
authors.initials: AC
authors.lastname: Bishop
authors.forename: K M
authors.initials: KM
authors.lastname: Shokat
authors.forename: M L
authors.initials: ML
authors.lastname: Thomas
authors.forename: C C
authors.initials: CC
authors.lastname: Goodnow
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D002645:Chickens; D051379:Mice; D008822:Mice, Transgenic; D009113:Muramidase / Q000276:immunology; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D017634:Self Tolerance; D015398:Signal Transduction
chemical_list: D011947:Receptors, Antigen, B-Cell; D009113:Muramidase