Isotype exclusion in lambda 1 transgenic mice depends on transgene copy number and diminishes with down-regulation of...

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.