A Human Immunoglobulin λ Locus Is Similarly Well Expressed in Mice and Humans

Abstract

Transgenic mice carrying a 380-kb region of the human immunoglobulin (Ig) λ light (L) chain locus in germline configuration were created. The introduced translocus on a yeast artificial chromosome (YAC) accommodates the most proximal Igλ variable region (V) gene cluster, including 15 Vλ genes that contribute to >60% of λ L chains in humans, all Jλ-Cλ segments, and the 3′ enhancer. HuIgλYAC mice were bred with animals in which mouse Igκ production was silenced by gene targeting. In the κ−/− background, human Igλ was expressed by ∼84% of splenic B cells. A striking result was that human Igλ was also produced at high levels in mice with normal κ locus. Analysis of bone marrow cells showed that human Igλ and mouse Igκ were expressed at similar levels throughout B cell development, suggesting that the Igλ translocus and the endogenous κ locus rearrange independently and with equal efficiency at the same developmental stage. This is further supported by the finding that in hybridomas expressing human Igλ the endogenous L chain loci were in germline configuration. The presence of somatic hypermutation in the human Vλ genes indicated that the Igλ-expressing cells function normally. The finding that human λ genes can be utilized with similar efficiency in mice and humans implies that L chain expression is critically dependent on the configuration of the locus.