A class switch control region at the 3′ end of the immunoglobulin heavy chain locus

Abstract

We replaced the IgH 3′ enhancer (3′E H) region with a neomycin resistance gene in ES cells and generated chimeric mice in which all mature lymphocytes were either heterozygous (3′E H +/−) or homozygous (3′E H −/−) for the mutation. In vitro activated 3′E H −/− B cells responded similarly to 3′E H +/− B cells with respect to proliferation and secretion of IgM and IgG1 but were specifically deficient in IgG2a, IgG2b, IgG3, and IgE secretion. These isotype deficiencies correlated with a deficiency in accumulation of transcripts from and class switching to affected C H genes. In vivo, chimeric mice containing only 3′E H −/− B cells were deficient in serum IgG2a and IgG3. We propose that the 3′E H −/− mutation disrupts the activity of a regulatory region that influences heavy chain class switching to several different C H genes that lie as far as 100 kb upstream of the mutation.