Regulation of repertoire development through genetic control of D H reading frame preference

Michael Zemlin, Robert L. Schelonka, Gregory C. Ippolito, Cosima Zemlin, Yingxin Zhuang, G. Larry Gartland, Lars Nitschke, Jukka Pelkonen, Klaus Rajewsky, Harry W. Schroeder

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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 receptorbased 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.

Original languageEnglish (US)
Pages (from-to)8416-8424
Number of pages9
JournalJournal of Immunology
Volume181
Issue number12
DOIs
StatePublished - Dec 15 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Zemlin, M., Schelonka, R. L., Ippolito, G. C., Zemlin, C., Zhuang, Y., Gartland, G. L., Nitschke, L., Pelkonen, J., Rajewsky, K., & Schroeder, H. W. (2008). Regulation of repertoire development through genetic control of D H reading frame preference. Journal of Immunology, 181(12), 8416-8424. https://doi.org/10.4049/jimmunol.181.12.8416