Genetic control of DH reading frame and its effect on B-cell development and antigen-specifc antibody production

Harry W. Schroeder, Michael Zemlin, Mohamed Khass, Huan H. Nguyen, Robert L. Schelonka

Research output: Contribution to journalReview article

31 Scopus citations

Abstract

The power of the adaptive immune system to identify novel antigens depends on the ability of lymphocytes to create antigen receptors with diverse antigen-binding sites. For immunoglobulins, CDR (complementarity-determining region)-H3 lies at the center of the antigen-binding site, where it often plays a key role in antigen binding. It is created de novo by VDJ rearrangement and is thus the focus for rearrangement-dependent diversity. CDR-H3 is biased for the inclusion of tyrosine. In seeking to identify the mechanisms controlling CDR-H3 amino acid content, we observed that the coding sequence of DH gene segments demonstrate conservation of reading frame (RF)-specific sequence motifs, with RF1 enriched for tyrosine and depleted of hydrophobic and charged amino acids. Use of DH RF1 in functional VDJ transcripts is preferred from the earliest stages of B-cell development, "pushing" CDR-H3 to include specific categories of tyrosine-enriched antigen-binding sites. With development and maturation, the composition of the CDR-H3 repertoire appears to be "pulled" into a more refined specific range. Forcing the use of alternative DH RFs by means of gene targeting alters the expressed repertoire, enriching alternative sequence categories. This change in the repertoire variably affects antibody production and the development of specific B-cell subsets.

Original languageEnglish (US)
Pages (from-to)327-344
Number of pages18
JournalCritical Reviews in Immunology
Volume30
Issue number4
StatePublished - 2010

Keywords

  • B-cell development
  • antibody repertoire
  • diversity gene segment
  • immunoglobulin

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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