A Role for Nuclear Factor Kappa B/Rel Transcription Factors in the Regulation of the Recombinase Activator Genes

Abstract

In developing B cells, expression of surface immunoglobulin is an important signal to terminate recombinase activator gene (RAG) expression and V(D)J recombination. However, autoreactive antigen receptors instead promote continued gene rearrangement and receptor editing. The regulation by B cell receptor (BCR) signaling of RAG expression and editing is poorly understood. We report that in editing-competent cells BCR ligand-induced RAG mRNA expression is regulated at the level of RAG transcription, rather than mRNA stability. In immature B cells carrying innocuous receptors, RAG expression appears to be under rapidly reversible negative regulation. Studies involving transduction of a superrepressive (sr) I kappa B alpha protein indicate that NF-kappaB/Rel proteins promote RAG transcription. Interestingly, NF kappa B1-deficient cells overexpress RAG and undergo an exaggerated receptor editing response. Our data implicate NF kappa B transcription factors in the BCR-mediated regulation of RAG locus transcription. Rapidly activated NF kappa B pathways may facilitate prompt antigen receptor-regulated changes in RAG expression important for editing and haplotype exclusion.

Receptor Editing Can Lead to Allelic Inclusion and Development of B Cells That Retain Antibodies Reacting with High Avidity Autoantigens

“…Clearly, additional studies are required to understand the qualitative, quantitative, and functional differences between Ag-mediated and tonic BCR signals in B cell development and selection. In accord with recent published work (47,49), our data suggest that these two signals have intrinsic qualitative differences that allow independent translation into distinct biological processes.…”

“…Ag binding and signaling by autoreactive BCRs on immature B cells have been shown to promote arrest of B cell differentiation (44,45) and induction of Rag expression and receptor editing (46,47). In contrast, the presence of a basal tonic signal delivered by presumably unbound (i.e., nonautoreactive) BCRs has been suggested to suppress Rag expression and mediate B cell differentiation and positive selection into the spleen (48,49).…”

NF-κB guides the survival and differentiation of developing lymphocytes

“…The surprising discovery was made that RAG gene expression is negatively regulated by NF-kB1 and positively regulated by RelA-and c-Rel-containing NF-kB dimmers. 17 These results suggest that weak/tonic signaling via the BCR may provide a positive selection signal that actively suppresses RAG expression (possibly via p50/NF-kB1 homodimers) thus preventing further rearrangement. p50 homodimers have previously been implicated in gene repression.…”

“…17 Immature B cells are the first stage at which developing B cells express a BCR (Figure 1). If a given BCR is autoreactive, the cell bearing it is either eliminated by apoptosis or reactivates RAG recombinase, so that it can 'edit' (further rearrange) the light chain to generate a different BCR.…”

FGD2, a CDC42-specific Exchange Factor Expressed by Antigen-presenting Cells, Localizes to Early Endosomes and Active Membrane Ruffles

“…Expression with Stimulation-Immature B cells from 3-83 BCR Tg mice were expanded from bone marrow using interleukin-7 cultures as described (27). One day after interleukin-7 removal, 20 g/ml either anti-BCR antibody (S23) or control (Y3) antibody was added to the cells for the indicated times.…”