Isotype exclusion in lambda 1 transgenic mice depends on transgene copy number and diminishes with down-regulation of transgene transcripts.
We have compared expression of the endogenous kappa and transgenic lambda 1 light chains in three lines of mice carrying one, four and eight copies of a lambda 1 transgene. We have found that in very young mice, even a single rearranged transgenic lambda allele excludes expression of the endogenous kappa loci. As the lambda 1 transgenic mice age, the proportion of lambda-positive cells decreases, as has been reported by others (Neuberger et al., Nature 1989, 338:350; Pettersson et al., Nature 1990. 344:165; Hagman et al., J. Exp. Med. 1989. 169:1911; Bogen and Weiss, Eur. J. Immunol. 1991. 21:2391). The decrease in lambda-positive B cells is accompanied by an increase in kappa-positive cells. We show that the decrease in B cells bearing surface lambda immunoglobulin depends on transgene copy number and occurs most rapidly in lower copy number lines. The decrease in surface lambda expression correlates with a dramatic decrease in the level of lambda mRNA in splenic B cells. Transgene down-regulation cannot be alleviated by stimulation of splenocytes with the mitogen lipopolysaccharide. These are the first data to establish that a single copy transgene can effect isotype exclusion. In addition, these results provide strong evidence that down-regulation of transgene expression is controlled at the level of transcription, and that it is the level of expressed light chain that regulates isotype exclusion.
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven.
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Hengstschläger
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Maizels
D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D015536:Down-Regulation / Q000276:immunology; D005434:Flow Cytometry; D007132:Immunoglobulin Isotypes / Q000235:genetics*; D007146:Immunoglobulin lambda-Chains / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D014158:Transcription, Genetic / Q000276:immunology*
D007132:Immunoglobulin Isotypes; D007146:Immunoglobulin lambda-Chains; D008070:Lipopolysaccharides