Extended Duration of DH–JH Rearrangement in Immunoglobulin Heavy Chain Transgenic Mice: Implications for Regulation of Allelic Exclusion

Abstract

Here we show that suppression of VH–DJH rearrangement in mice bearing a μ heavy (H) chain transgene (μ-tg mice) is associated with an extended period of DH–JH rearrangement, the first step of Immunoglobulin H chain gene rearrangement. Whereas DH–JH rearrangement is normally initiated and completed at the pro-B cell stage, in μ-tg mice it continues beyond this stage and occurs most frequently at the small (late) pre-B stage. Despite ongoing DH–JH rearrangement in late pre-B cells of μ-tg mice, VH–DJH rearrangement is not detectable in these cells. We infer that the lack of VH–DJH rearrangement primarily reflects tg-induced acceleration of B cell differentiation past the stage at which rearrangement of VH elements is permissible. In support of this inference, we find that the normal representation of early B lineage subsets is markedly altered in μ-tg mice. We suggest that the effect of a productive VH–DJH rearrangement at an endogenous H chain allele may be similar to that of a μ-tg; i.e., cells that make a productive VH–DJH rearrangement on the first attempt rapidly progress to a developmental stage that precludes VH–DJH rearrangement at the other allele (allelic exclusion).