A λ1 transgene under the control of a heavy chain promoter and enhancer does not undergo somatic hypermutation

Abstract

To identify cis-acting elements responsible for targeting somatic hypermutation to immunoglobulin variable regions, we generated transgenic mice which carry a rearranged λ1 gene regulated by the heavy chain intron enhancer, Eμ, and the heavy chain promoter P_H186.2 from the V_H186.2 variable region. C57BL/6 × SJL founders were bred with C57BL/6 mice to establish a line carrying a single copy of the transgene. Somatic hypermutation was studied by generating hybridoma cell lines from mice immunized with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken gamma globulin. The immune response in this transgenic line was dominated by the endogenous V_H186.2 heavy chain variable region and the transgenic λ1 light chain, and the transgene was actively expressed in all hybridomas analyzed. In this work we show that the transgenic Vλ1 regions do not undergo hypermutation, despite high levels of expression, while the expressed heavy chain V regions accumulate mutations at a rate typical of the NP response in C57BL/6 mice. Thus, within the same B cell, the P_H186.2 promoter in connection with E_μ drives efficient expression of both a V_H and a Vλ region, but only the V_H is a target for somatic hypermutation. Our observations show that cis-acting sequences that activate immunoglobulin gene transcription are not sufficient to target somatic hypermutation.