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* Department of Medicine, Department of Microbiology, Department of Genetics, Department of Pediatric Dentistry, and Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294;
Department of Pediatrics, Philipps Universität Marburg, Marburg, Germany, and
Immune Disease Institute, Harvard Medical School, Boston, MA 02115
All jawed vertebrates limit use of DH reading frames (RFs) that are enriched for hydrophobic amino acids. In BALB/c mice, DFL16.1 RF2 encodes valine and isoleucine. To test whether increased use of RF2 affects B cell function, we examined B cell development and Ab production in mice with an IgH allele (
D-DµFS) limited to use of a single, frameshifted DFL61.1 gene segment. We compared the results of these studies to wild-type mice, as well as those previously obtained in mice limited to use of either a single normal DH or a single inverted DH that forces use of arginine in CDR-H3. All three of the mouse strains limited to a single DH produced fewer immature B cells than wild type. However, whereas mice limited to a single normal DH achieved normal B cell numbers in the periphery, mice forced to preferentially use RF2 had reduced numbers of mature B cells in the spleen and bone marrow, mirroring the pattern previously observed in mice enriched for charged CDR-H3s. There were two exceptions. B cells in the mice using RF2 normally populated the marginal zone and peritoneal cavity, whereas mice using inverted RF1 had increased numbers of marginal zone B cells and decreased numbers of B1a cells. When challenged with several T-dependent or T-independent Ags, Ag-specific Ab titers in the mice forced to use RF2 were altered. These findings indicate that B cell development and Ag-specific Ab production can be heavily influenced by the global amino acid content of the CDR-H3 repertoire.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants AI07051, AI42732, AI48115, HD043327, and TW02130; by Deutsche Forschungsgemeinschaft Grant SFB/TR22-TPA17; and by Alexander von Humboldt-Stiftung FLF1071857.
2 R.L.S. and M.Z. contributed equally to this work
3 Address correspondence and reprint requests to Dr. Harry W. Schroeder, Jr., University of Alabama at Birmingham, Shelby Building 176, Third Avenue South, Birmingham, AL 35294. E-mail address: hwsj{at}uab.edu
4 Abbreviations used in this paper: CDR-H3, Ig H chain CDR 3; ANA, antinuclear Ab; D, depleted DH locus; DEX, 
(1
3)-dextran; DFL, single DFL16.1 gene segment; DµFS, single frameshifted DFL15.1 gene segment; iD, mutated DFL16.1 gene segment with inverted DSP 2.2 sequence; MZ, marginal zone; MPER, membrane-proximal external region; NP, (4-hydroxy-3-nitrophenyl)acetyl hapten; NP19CGG, NP-chicken gamma globulin; RF, reading frame; TT, tetanus toxoid.
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  M. Zemlin, R. L. Schelonka, G. C. Ippolito, C. Zemlin, Y. Zhuang, G. L. Gartland, L. Nitschke, J. Pelkonen, K. Rajewsky, and H. W. Schroeder Jr. Regulation of Repertoire Development through Genetic Control of DH Reading Frame Preference J. Immunol., December 15, 2008; 181(12): 8416 - 8424. [Abstract] [Full Text] [PDF]
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