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V_H Replacement Rescues Progenitor B Cells with Two Nonproductive VDJ Alleles¹

Johannes Lutz^*, Werner Müller and Hans-Martin Jäck^2,*

^* Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center of Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; and Department of Experimental Immunology, German Research Centre for Biotechnology, Braunschweig, Germany

Inaccurate VDJ rearrangements generate a large number of progenitor (pro)-B cells with two nonproductive IgH alleles. Such cells lack essential survival signals mediated by surface IgM heavy chain (µH chain) expression and are normally eliminated. However, secondary rearrangements of upstream V_H gene segments into assembled VDJ exons have been described in mice transgenic for productive µH chains, a process known as V_H replacement. If V_H replacement was independent of µH chain signals, it could also modify nonproductive VDJ exons and thus rescue pro-B cells with unsuccessful rearrangements on both alleles. To test this hypothesis, we homologously replaced the J_H cluster of a mouse with a nonproductive VDJ exon. Surprisingly, B cell development in IgH^{VDJ–/VDJ–} mice was only slightly impaired and significant numbers of IgM-positive B cells were produced. DNA sequencing confirmed that all VDJ sequences from µH chain-positive B lymphoid cells were generated by V_H replacement in a RAG-dependent manner. Another unique feature of our transgenic mice was the presence of IgH chains with unusually long CDR3-H regions. Such IgH chains were functional and only modestly counter-selected, arguing against a strict length constraint for CDR3-H regions. In conclusion, V_H replacement can occur in the absence of a µH chain signal and provides a potential rescue mechanism for pro-B cells with two nonproductive IgH alleles.

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 The work was supported in part by the Project Grant SFB466 and the Research Grant JA 968/2 from the Deutsche Forschungsgemeinschaft (to H.-M.J.) and by the German National Genome Network Grant 01GR0439 (to W.M.).

² Address correspondence and reprint requests to Dr. Hans-Martin Jäck, Division of Molecular Immunology, Nikolaus-Fiebiger-Center of Molecular Medicine, Friedrich-Alexander-University of Erlangen-Nürnberg, Glückstrasse 6, D-91054 Erlangen, Germany. E-mail address: hjaeck{at}molmed.uni-erlangen.de

³ Abbreviations used in this paper: RSS, recombination signal sequence; cRSS, cryptic RSS; pro, progenitor; µH chain, IgM heavy chain; ES, embryonic stem.

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