Processing of switch transcripts is required for targeting of antibody class switch recombination

Antibody class switching is mediated by somatic recombination between switc h regions of the immunoglobulin heavy chain gene locus. Targeting of recomb ination to particular switch regions is strictly regulated by cytokines thr ough the: induction of switch transcripts starting 5' of the repetitive swi tch regions. However, switch transcription as such is not sufficient to tar get switch recombination. This has been shown in mutant mice, in which the I-exon and its promoter upstream of the switch region wt rr replaced with h eterologous promoters. Here we show that, in the murine germline targeted r eplacement of the endogenous gamma 1 promoter, I-exon, and I-exon splice do nor site by heterologous promoter and splice donor sites directs switch rec ombination in activated B lymphocytes constitutively to the gamma 1 switch region. In contrast, switch recombination to IgG1 is inhibited in mutant mi ce, in which the replacement does riot include the heterologous splice dono r rite. Our data unequivocally demonstrate that targeting of switch recombi nation to IgG1 in vivo requires processing of the I gamma 1 switch transcri pts, either the processing machinery or the processed transcripts are invol ved in class switch recombination.