DELETION OF THE IMMUNOGLOBULIN KAPPA-CHAIN INTRON ENHANCER ABOLISHES KAPPA-CHAIN GENE REARRANGEMENT IN CIS BUT NOT LAMBDA-CHAIN GENE REARRANGEMENT IN TRANS

Immunoglobulins (Ig) secreted from a plasma cell contain either chi or lambda light chains, but not both. This phenomenon is termed isotypic chi-lambda exclusion. While chi-producing cells have their lambda cha in genes in germline configuration, in most lambda-producing cells the chi chain genes are either non-productively rearranged or deleted. To investigate the molecular mechanism for isotypic chi-lambda exclusion , in particular the role of the Igchi intron enhancer, we replaced thi s enhancer by a neomycin resistance (neo(R)) gene in embryonic stem (E S) cells. B cells heterozygous for the mutation undergo Vchi-Jchi reco mbination exclusively in the intact Igchi locus but not in the mutated Igchi locus. Homozygous mutant mice exhibited no rearrangements in th eir Igchi loci. However, splenic B cell numbers were only slightly red uced as compared with the wild-type, and all B cells expressed lambda chain bearing surface Ig. These findings demonstrate that rearrangemen t in the Igchi locus is not essential for lambda gene rearrangement. W e also generated homozygous mutant mice in which the neo(R) gene was i nserted at the 3' end of the Igchi intron enhancer. Unexpectedly, mere insertion of the neo(R) gene showed some suppressive effect on Vchi-J chi recombination. However, the much more pronounced inhibition of Vch i-Jchi recombination by the replacement of the Igchi intron enhancer s uggests that this enhancer is essential for Vchi-Jchi recombination.