The Journal of Experimental Medicine
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Published online 20 March 2000.
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© The Rockefeller University Press, 0022-1007/2000/3/1031/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 6, March 20, 2000 1031-1044

Original Article

Gene Dose–Dependent Maturation and Receptor Editing of B Cells Expressing Immunoglobulin (Ig)g1 or Igm/Igg1 Tail Antigen Receptors

Sarah L. Poguea and Christopher C. Goodnowb

a Department of Microbiology and Immunology and Howard Hughes Medical Institute, Stanford University, Palo Alto, California 94305
b Medical Genome Centre, Australian Cancer Research Foundation Genetics Laboratory, John Curtin School of Medical Research, Australian National University Canberra, Canberra ACT 2601, Australia
John Curtin School of Medical Research, Mills Rd., Australian National University, P.O. Box 334, Canberra ACT 2601, Australia.61-2-6279-851261-2-6249-3621

Chris.Goodnow{at}anu.edu.au

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 CD21high 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.

Key Words: B lymphocyte • development • isotype switch • allelic exclusion • transgene

Abbreviations used in this paper: BCR, B cell antigen receptor; Hc, heavy chain; HEL, hen egg lysozyme; Lc, light chain; RAG, recombinase activating gene; SHP, Src homology 2 domain–containing protein tyrosine phosphatase; Tg, transgene.

© 2000 The Rockefeller University Press


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