Cellular selection leads to age-dependent and reversible down-regulation of transgenic immunoglobulin light chain genes.

Analysis of immunoglobulin expression in mice transgenic for either a kappa light chain (driven by the kappa enhancer) or lambda light chain (driven by the IgH enhancer) revealed that the transgenic light chains are expressed by the majority of B lymphocytes in the neonatal mice. However, the proportion of B cells that express the transgenes at a detectable level decreases rapidly with age, with a concomitant increase in cells expressing rearrangements of one of the endogenous light chain loci. This appears to be the result of cellular selection. The down-regulation of transgene expression is not due to an irreversible mechanism as incubation of adult splenic lymphocytes with bacterial lipopolysaccharide leads to a rapid increase in the expression of the transgenic light chain on the B cell surface. In mice carrying the lambda transgene (but not in mice carrying the kappa transgene) the change with age in the pattern of transgene expression is accompanied by a shift towards B cells that do not express surface IgD. This shift towards IgM+/IgDlow B cells is also observed in mice transgenic for a chloramphenicol acetyltransferase gene linked to the IgH enhancer. This suggests that the down-regulation of IgD may either be due to the expression of a transgene that impairs B cell development or, alternatively, could be associated with the molecular events responsible for the down-regulation of IgH enhancer activity. The results also draw attention to the contribution of cellular selection in determining the pattern of expression of immunoglobulin transgenes and emphasize the importance of in vivo analysis of neonatal as well as adult transgenic mice.