Interallelic Class Switch Recombination Contributes Significantly to Class Switching in Mouse B Cells

Abstract

Except for the expression of IgM and IgD, DNA recombination is constantly needed for the expression of other Ig classes and subclasses. The predominant path of class switch recombination (CSR) is intrachromosomal, and the looping-out and deletion model has been abundantly documented. However, switch regions also occasionally constitute convenient substrates for interchromosomal recombination, since it is noticeably the case in a number of chromosomal translocations causing oncogene deregulation in the course of lymphoma and myeloma. Although asymmetric accessibility of Ig alleles should theoretically limit its occurrence, interallelic CSR was shown to occur at low levels during IgA switching in rabbit, where the definition of allotypes within both V and C regions helped identify interchromosomally derived Ig. Thus, we wished to evaluate precisely interallelic CSR frequency in mouse B cells, by using a system in which only one allele (of b allotype) could express a functional VDJ region, whereas only interallelic CSR could restore expression of an excluded (a allotype) allele. In our study, we show that interchromosomal recombination of VH and Cγ or Cα occurs in vivo in B cells at a frequency that makes a significant contribution to physiological class switching: trans-association of VH and CH genes accounted for 7% of all α mRNA, and this frequency was about twice higher for the γ3 transcripts, despite the much shorter distance between the JH region and the Cγ3 gene, thus confirming that this phenomenon corresponded to site-specific switching and not to random recombination between long homologous loci.