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* Department of Pediatrics, Philipps Universität Marburg, Marburg, Germany;
Departments of Medicine, Microbiology, Genetics, Pediatric Dentistry, and Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294;
Department of Genetics, Universität Erlangen, Erlangen, Germany;
Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland; and
¶ Immune Disease Institute, Harvard Medical School, Boston, MA 02115
In jawed vertebrates most expressed Ig H chains use only one of six possible DH reading frames. Reading frame (RF)1, the preferred reading frame, tends to encode tyrosine and glycine, whereas the other five RFs tend to be enriched for either hydrophobic or charged amino acids. Mechanisms proposed to favor use of RF1 include a preference for deletion over inversion that discourages use of inverted RF1, RF2, and RF3; sequence homology between the 5' terminus of the JH and the 3' terminus of the DH that promotes rearrangement into RF1; an ATG start site upstream of RF2 that permits production of a truncated Dµ protein; stop codons in RF3; and, following surface expression of IgM, somatic, presumably Ag receptor-based selection favoring B cells expressing Igs with tyrosine- and glycine-enriched CDR-H3s. By creating an IgH allele limited to the use of a single, frameshifted DFL16.1 DH gene segment, we tested the relative contribution of these mechanisms in determining reading frame preference. Dµ-mediated suppression via an allelic exclusion-like mechanism dominated over somatic selection in determining the composition of the CDR-H3 repertoire. Evidence of somatic selection for RF1-encoded tyrosine in CDR-H3 was observed, but only among the minority of recirculating, mature B cells that use DH in RF1. These observations underscore the extent to which the sequence of the DH acts to delimit the diversity of the Ab repertoire.
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1 This work was supported in part by National Institutes of Health Grants AI07051, AI42732, AI48115, HD043327, and TW02130; by Deutsche Forschungsgemeinschaft SFB/TR22-TPA17; and by Alexander von Humboldt-Stiftung FLF1071857.
2 M.Z. and R.L.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Harry W. Schroeder, Jr., Departments of Medicine, Microbiology, Genetics, Pediatric Dentistry, and Pediatrics, University of Alabama at Birmingham, Shelby Building 176, 1530 3rd Avenue South, Birmingham, AL 35294. E-mail address: hwsj{at}uab.edu
4 Abbreviations used in this paper: RF, DH reading frame; 
D-DFL, depleted DH locus with a single DFL16.1 gene segment; D-iD, depleted DH locus with a single, mutated DFL16.1 gene segment containing inverted DSP2.2sequence; D-DµFS, depleted DH locus with a single, frameshifted DFL16.1 gene segment; CDR-H3, Ig heavy-chain CDR3; ES, embryonic stem; ORF, open reading frame; RSS, recombination signal sequence.
5 The online version of this article contains supplemental material.
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  R. L. Schelonka, M. Zemlin, R. Kobayashi, G. C. Ippolito, Y. Zhuang, G. L. Gartland, A. Szalai, K. Fujihashi, K. Rajewsky, and H. W. Schroeder Jr. Preferential Use of DH Reading Frame 2 Alters B Cell Development and Antigen-Specific Antibody Production J. Immunol., December 15, 2008; 181(12): 8409 - 8415. [Abstract] [Full Text] [PDF]
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