title: Different nuclear signals are activated by the B cell receptor during positive versus negative signaling.
abstract: It is not known how immunogenic versus tolerogenic cellular responses are signaled by receptors such as the B cell antigen receptor (BCR). Here we compare BCR signaling in naive cells that respond positively to foreign antigen and self-tolerant cells that respond negatively to self-antigen. In naive cells, foreign antigen triggered a large biphasic calcium response and activated nuclear signals through NF-AT, NF-kappa B, JNK, and ERK/pp90rsk. In tolerant B cells, self-antigen stimulated low calcium oscillations and activated NF-AT and ERK/pp90rsk but not NF-kappa B or JNK. Self-reactive B cells lacking the phosphatase CD45 did not exhibit calcium oscillations or ERK/pp90rsk activation, nor did they repond negatively to self-antigen. These data reveal striking biochemical differences in BCR signaling to the nucleus during positive selection by foreign antigens and negative selection by self-antigens.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, California 94305, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Healy
authors.forename: R E
authors.initials: RE
authors.lastname: Dolmetsch
authors.forename: L A
authors.initials: LA
authors.lastname: Timmerman
authors.forename: J G
authors.initials: JG
authors.lastname: Cyster
authors.forename: M L
authors.initials: ML
authors.lastname: Thomas
authors.forename: G R
authors.initials: GR
authors.lastname: Crabtree
authors.forename: R S
authors.initials: RS
authors.lastname: Lewis
authors.forename: C C
authors.initials: CC
authors.lastname: Goodnow
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001692:Biological Transport / Q000276:immunology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis; D002467:Cell Nucleus / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000276:immunology; D017874:Immediate-Early Proteins; D007108:Immune Tolerance; D017493:Leukocyte Common Antigens / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1; D016328:NF-kappa B / Q000096:biosynthesis; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011947:Receptors, Antigen, B-Cell; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D017493:Leukocyte Common Antigens; D002118:Calcium