Gene dose-dependent maturation and receptor editing of B cells expressing immunoglobulin (Ig)G1 or IgM/IgG1 tail antigen receptors.
Conserved differences between the transmembrane and cytoplasmic domains of membrane immunoglobulin (Ig)M and IgG may alter the function of antigen receptors on naive versus memory B cells. Here, we compare the ability of these domains to signal B cell allelic exclusion and maturation in transgenic mice. A lysozyme-binding antibody was expressed in parallel sets of mice as IgM, IgG1, or a chimeric receptor with IgM extracellular domains and transmembrane/cytoplasmic domains of IgG1. Like IgM, the IgG1 or chimeric IgM/G receptors triggered heavy chain allelic exclusion and supported development of mature CD21(+) B cells. Many of the IgG or IgM/G B cells became CD21(high) and downregulated their IgG and IgM/G receptors spontaneously, resembling memory B cells and B cells with mutations that exaggerate B cell antigen receptor signaling. Unlike IgM-transgenic mice, "edited" B cells that carry non-hen egg lysozyme binding receptors preferentially accumulated in IgG and IgM/G mice. This was most extreme in lines with the highest transgene copy number and diminished in variant offspring with fewer copies. The sensitivity of B cell maturation to transgene copy number conferred by the IgG transmembrane and cytoplasmic domains may explain the diverse phenotypes found in other IgG-transgenic mouse strains and may reflect exaggerated signaling.
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Department of Microbiology and Immunology and Howard Hughes Medical Institute, Stanford University, Palo Alto, California 94305, USA.
Goodnow
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D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002645:Chickens; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D018628:Gene Dosage; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D007075:Immunoglobulin M / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009113:Muramidase / Q000378:metabolism; D017393:RNA Editing / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism; D011961:Receptors, Fc / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism; D019895:Transposases / Q000172:deficiency / Q000235:genetics
D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C064655:V(D)J recombination activating protein 2; C035311:immunoglobulin M receptor; D019895:Transposases; D009113:Muramidase