Immunoglobulin β signaling regulates locus accessibility for ordered immunoglobulin gene rearrangements

Abstract

The antigen receptor gene rearrangement at a given locus is tightly regulated with respect to cell lineage and developmental stage by an ill- defined mechanism. To study the possible role of precursor B cell antigen receptor (pre-BCR) signaling in the regulation of the ordered immunoglobulin (Ig) gene rearrangement during B cell differentiation, a newly developed system using μ heavy (H) chain membrane exon (μm)-deficient mice was employed. In this system, the antibody-mediated cross-linking of Igβ on developmentally arrested progenitor B (pro-B) cells mimicked pre-BCR signaling to induce early B cell differentiation in vivo. Analyses with ligation-mediated polymerase chain reaction revealed that the Igβ cross- linking induced the redirection of Ig gene rearrangements, namely, the suppression of ongoing rearrangements at the H chain locus and the activation of rearrangements at the light (L) chain locus. Upon the crosslinking, the κL chain germline transcription was found to be upregulated whereas the V(H) germline transcription was promptly downregulated. Notably, this alteration of the accessibility at the H and L chain loci was detected even before the induction of cellular differentiation became detectable by the change of surface phenotype. Thus, the pre-BCR signaling through Igβ appears to regulate the ordered Ig gene rearrangement by altering the Ig locus accessibility.