Isotype exclusion and transgene down-regulation in immunoglobulin-λ transgenic mice

Abstract

A GIVEN B lymphocyte makes an antibody containing either κ-or λ-light chains, but not both1,2. This isotype exclusion is effected at the level of the rearrangement of the immunoglobulin gene segments3–5, although by an unknown mechanism. An attractive possibility is that, following productive rearrangement of one of the light-chain loci, the newly synthesized light-chain polypeptide inhibits DNA rearrangement for the other isotype. To test such feedback regulation, we have created transgenic mice carrying a rearranged λ1-gene. By contrast with the B cells in normal newborn mice which are mainly κ+λ−, the B cells in the newborn transgenic mice express λ- but not κ-chains. We propose that the synthesis of any light chain, be it κ or λ, that allows expression of IgM on the cell surface results in a cessation of all V–J joining. Interestingly, the limited light-chain repertoire of the transgenic mice does not persist and most adult B cells express endogenous κ-rearrangements and down-regulate the transgene.