SUBTLE DIFFERENCES IN ANTIBODY-RESPONSES AND HYPERMUTATION OF LAMBDA-LIGHT CHAINS IN MICE WITH A DISRUPTED CHI CONSTANT-REGION

Analysis of lambda light chain use in normal mice is made difficult by the dominant kappa light chain repertoire. We produced mice rendered deficient in kappa light chain expression by gene targeting and focuse d on questions concerned with the generation of lambda light chain div ersity. Whilst these mice compensate the kappa deficiency with increas ed lambda titers, and their Ig level is therefore not significantly re duced, they show major differences in immunization titers, germinal ce nter (GC) development and somatic hypermutation. After immunization, u sing antigens that elicit a restricted IgL response in normal mice, we obtained in the kappa(+) mice elevated primary antibody titers but a subsequent lack in titer increase after repeated antigen challenge. An alysis of the Peyer's patches (PP) revealed a dramatically reduced cel l content with rather small but highly active GC. Flow cytometric anal ysis showed different cell populations in the PP with enriched peanut agglutinin (PNA)(hi)/CD45R(B220)(+) B cells, implying that the apparen t compensation for the lack of kappa light chain expression involves t he GC microenvironment in cell selection, the initiation of hypermutat ion and high affinity expansion. The three V lambda genes, V1, V2 and Vx, are mutated in the GC B cells, but show no junctional diversity. I n contrast, a reduced rate of V kappa hypermutation is found in the hy bridoma antibodies, which appears to reflect a selection bias rather t han structural constraints. However, mechanisms of somatic mutation an d specificity selection can operate with equal efficiency on the few V kappa genes.