RNA exosome drives early B cell development via noncoding RNA processing mechanisms

Abstract

B cell development is linked to successful V(D)J recombination, allowing B cell receptor expression and ultimately antibody secretion for adaptive immunity. Germline noncoding RNAs (ncRNAs) are produced at immunoglobulin (Ig) loci during V(D)J recombination, but their function and posttranscriptional regulation are incompletely understood. Patients with trichohepatoenteric syndrome, characterized by RNA exosome pathway component mutations, exhibit lymphopenia, thus demonstrating the importance of ncRNA surveillance in B cell development in humans. To understand the role of RNA exosome in early B cell development in greater detail, we generated mouse models harboring a B cell–specific cre allele ( Mb1 cre ), coupled to conditional inversion-deletion alleles of one RNA exosome core component ( Exosc3 ) or RNase catalytic subunits ( Exosc10 or Dis3 ). We noticed increased expression of RNA exosome subunits during V(D)J recombination, whereas a B cell developmental blockade at the pro–B cell stage was observed in the different knockout mice, overlapping with a lack of productive rearrangements of VDJ genes at the Ig heavy chain ( Igh ). This unsuccessful recombination prevented differentiation into pre–B cells, with accumulation of ncRNAs and up-regulation of the p53 pathway. Introduction of a prearranged Igh VDJ allele partly rescued the pre–B cell population in Dis3 -deficient cells, although V-J recombination defects were observed at Ig light chain kappa ( Ig κ), preventing subsequent B cell development. These observations demonstrated that the RNA exosome complex is important for Igh and Ig κ recombination and establish the relevance of RNA processing for optimal diversification at these loci during B cell development.