CROSSING THE SJL LAMBDA-LOCUS INTO KAPPA-KNOCKOUT MICE REVEALS A DYSFUNCTION OF THE LAMBDA-1-CONTAINING IMMUNOGLOBULIN RECEPTOR IN B-CELL DIFFERENTIATION

Mice of the SJL strain produce similar to 50 times less serum lambda 1 immunoglobulin light chains than other mouse strains. The defect is g enetically linked to the lambda locus, but it is unknown whether it is due to regulatory alterations or known structural changes. We find no mutation in the SJL lambda 3-1 enhancer which regulates both lambda 1 and lambda 3. To investigate the defect further, the production of la mbda light chains was amplified by crossing SJL with kappa-knockout mi ce. In kappa-knockout mice with the wildtype lambda locus (kappa-/- la mbda+/+), the majority of serum light chains are lambda 1. In contrast , kappa-knockout mice with the SJL lambda locus (kappa-/- lambda s/s) show a pronounced expression of lambda 2 and lambda 3, with only some expression of lambda 1. The results show that the SJL defect is lambda 1 specific, since the linked lambda 3 expression is normal. As the tr anscription and rearrangement of lambda 1 appear normal in SJL, the de fective lambda 1 synthesis is most likely due to a point mutation in t he lambda 1 constant region resulting in a glycine to valine substitut ion. At the cellular level, in kappa-knockout mice with the SJL lambda locus there are fewer immature, and especially mature, lambda 1 B cel ls and the production of lambda 1 plasma cells is strongly inhibited. The lambda 1 specificity of the defect suggests that the point mutatio n in SJL C lambda 1 creates an immunoglobulin receptor complex which i s dysfunctional in B cell differentiation.