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S3 switch sequences function in place of endogenous S1 to mediate antibody class switching

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 (C_H) exons. Individual sets of C_H 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 S1 region was replaced with wild-type (WT) or synthetic 2-kb S3 sequences or a synthetic 2-kb S1 sequence. We found that both the inserted endogenous and synthetic S3 sequences functioned similarly to a size-matched synthetic S1 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 S3 can function similarly to S1 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.

© 2008 Zarrin et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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