The Journal of Experimental Medicine
Keystone Symposia
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Published online June 9, 2008
doi:10.1084/jem.20080451
The Journal of Experimental Medicine, Vol. 205, No. 7, 1567-1572
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Zarrin et al.
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BRIEF DEFINITIVE REPORT

 S{gamma}3 switch sequences function in place of endogenous S{gamma}1 to mediate antibody class switching

Ali A. Zarrin1, Peter H. Goff1, Kate Senger2, and Frederick W. Alt1

1 Howard Hughes Medical Institute, Children's Hospital, Immune Disease Institute, and Department of Genetics, Harvard University Medical School, Boston, MA 02115
2 Immunology Discovery Group, Genentech Inc., South San Francisco, CA 94080

CORRESPONDENCE Frederick W. Alt: alt{at}enders.tch.harvard.edu

Immunoglobulin heavy chain (IgH) class switch recombination (CSR) replaces the initially expressed IgH Cµ exons with a set of downstream IgH constant region (CH) exons. Individual sets of CH exons are flanked upstream by long (1–10-kb) repetitive switch (S) regions, with CSR involving a deletional recombination event between the donor Sµ region and a downstream S region. Targeting CSR to specific S regions might be mediated by S region–specific factors. To test the role of endogenous S region sequences in targeting specific CSR events, we generated mutant B cells in which the endogenous 10-kb S{gamma}1 region was replaced with wild-type (WT) or synthetic 2-kb S{gamma}3 sequences or a synthetic 2-kb S{gamma}1 sequence. We found that both the inserted endogenous and synthetic S{gamma}3 sequences functioned similarly to a size-matched synthetic S{gamma}1 sequence to mediate substantial CSR to IgG1 in mutant B cells activated under conditions that stimulate IgG1 switching in WT B cells. We conclude that S{gamma}3 can function similarly to S{gamma}1 in mediating endogenous CSR to IgG1. The approach that we have developed will facilitate assays for IgH isotype–specific functions of other endogenous S regions.

A.A. Zarrin's present address is Immunology Discovery Group, Genentech Inc., South San Francisco, CA 94080.


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