The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/12/2369/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 12, December 21, 1998 2369-2374

Brief Definitive Reports

Processing of Switch Transcripts Is Required for Targeting of Antibody Class Switch Recombination

Katharina Hein*, Matthias G.O. Lorenz{ddagger}, Gregor Siebenkotten§, Katja Petry*, Rainer Christine*, and Andreas Radbruch*

From the * Deutsches Rheuma-Forschungszentrum Berlin, 10115 Berlin, Germany; {ddagger} the National Institutes of Health, National Cancer Institute, Laboratory of Tumor Immunology and Biology, Bethesda, Maryland 20892; and § AMAXA GmbH, c/o Deutsches Rheuma-Forschungszentrum Berlin, 10115 Berlin, Germany

Antibody class switching is mediated by somatic recombination between switch regions of the immunoglobulin heavy chain gene locus. Targeting of recombination to particular switch regions is strictly regulated by cytokines through the induction of switch transcripts starting 5' of the repetitive switch regions. However, switch transcription as such is not sufficient to target switch recombination. This has been shown in mutant mice, in which the I-exon and its promoter upstream of the switch region were replaced with heterologous promoters. Here we show that, in the murine germline targeted replacement of the endogenous {gamma}1 promoter, I-exon, and I-exon splice donor site by heterologous promoter and splice donor sites directs switch recombination in activated B lymphocytes constitutively to the {gamma}1 switch region. In contrast, switch recombination to IgG1 is inhibited in mutant mice, in which the replacement does not include the heterologous splice donor site. Our data unequivocally demonstrate that targeting of switch recombination to IgG1 in vivo requires processing of the I{gamma}1 switch transcripts. Either the processing machinery or the processed transcripts are involved in class switch recombination.

Key Words: class switch • recombination • splicing • switch transcript • B lymphocytes

Address correspondence to Andreas Radbruch, Deutsches Rheuma-Forschungszentrum Berlin, Hannoversche Strasse 27, 10115 Berlin, Germany. Phone: 0049-30-2851-8980; Fax: 0049-30-2851-8910; E-mail: radbruch @drfz.de


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