Selection of individual VH genes occurs at the pro-B to pre-B cell transition

J Immunol. 2011 Aug 15;187(4):1835-44. doi: 10.4049/jimmunol.1100207. Epub 2011 Jul 11.

Abstract

B cells are subjected to selection at multiple checkpoints during their development. The selection of Ab H chains is difficult to study because of the large diversity of the CDR3. To study the selection of individual Ab H chain V region genes (V(H)), we performed CDR3 spectratyping of ∼ 75-300 rearrangements per individual V(H) in C57BL6/J mice. We measured the fraction of rearrangements that were in-frame in B cell DNA. We demonstrate that individual V(H)s have different fractions of in-frame rearrangements (IF fractions) ranging from 10 to 90% and that these IF fractions are reproducible in different mice. For most V(H)s, the IF fraction in pro-B cells approximated 33% and then shifted to the nearly final (mature) B cell value by the cycling pre-B cell stage. The frequency of high in-frame (IF) V(H) usage increased in cycling pre-B cells compared with that in pro-B cells, whereas this did not occur for low IF V(H)s. The IF fraction did not shift as much in BCR-expressing B cells and was minimally affected by L chain usage for most V(H). High IF clan II/III V(H)s share more positively charged CDR2 sequences, whereas high IF clan I J558 CDR2 sequences are diverse. These data indicate that individual V(H)s are subjected to differential selection, that V(H) IF fraction is mainly established through pre-BCR-mediated selection, that it may operate differently in clan I versus II/III V(H)s, and that it has a lasting influence on the Ab repertoire.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology
  • Complementarity Determining Regions / metabolism*
  • DNA / genetics
  • DNA / immunology
  • DNA / metabolism*
  • Gene Expression Regulation / physiology
  • Mice
  • Precursor Cells, B-Lymphoid / cytology
  • Precursor Cells, B-Lymphoid / immunology
  • Precursor Cells, B-Lymphoid / metabolism*
  • Proto-Oncogene Proteins c-bcr / biosynthesis
  • Proto-Oncogene Proteins c-bcr / genetics
  • Proto-Oncogene Proteins c-bcr / immunology
  • Somatic Hypermutation, Immunoglobulin / physiology*

Substances

  • Complementarity Determining Regions
  • DNA
  • Bcr protein, mouse
  • Proto-Oncogene Proteins c-bcr