Deletion of the immunoglobulin kappa chain intron enhancer abolishes kappa chain gene rearrangement in cis but not lambda chain gene rearrangement in trans.

Abstract

Immunoglobulins (Ig) secreted from a plasma cell contain either κ orλ light chains, but not both. This phenomenon is termed isotypic κ-λ exclusion. While κ-producing cells have their λ chain genes in germline configuration, in most λ-producing cells the κ chain genes are either nonproductively rearranged or deleted. To investigate the molecular mechanism for isotypic λ exclusion, in particular the role of the Igκ intron enhancer, we replaced this enhancer by a neomycin resistance (neo(R)) gene in embryonic stem (ES) cells. B cells heterozygous for the mutation undergo Vκ-Jκ recombination exclusively in the intact Igκ locus but not in the mutated Igκ locus. Homozygous mutant mice exhibited no rearrangements in their Igκ loci. However, splenic B cell numbers were only slightly reduced as compared with the wild-type, and all B cells expressed λ chain bearing surface Ig. These findings demonstrate that rearrangement in the Igκ locus is not essential for λ gene rearrangement. We also generated homozygous mutant mice in which the neo(R) gene was inserted at the 3' end of the Igκ intron enhancer. Unexpectedly, mere insertion of the neo(R) gene showed some suppressive effect on VκxJκ recombination. However, the much more pronounced inhibition of Vκ-Jκ recombination by the replacement of the Igκ intron enhancer suggests that this enhancer is essential for Vκ-Jκ recombination.