IFN Regulatory Factor 4 and 8 Promote Ig Light Chain κ Locus Activation in Pre-B Cell Development

Abstract

Previous studies have shown that B cell development is blocked at the pre-B cell stage in IFN regulatory factor (IRF)4 (pip) and IRF8 (IFN consensus sequence binding protein) double mutant mice (IRF4,8−/−). In this study, the molecular mechanism by which IRF4,8 regulate pre-B cell development was further investigated. We show that IRF4,8 function in a B cell intrinsic manner to control pre-B cell development. IRF4,8−/− mice expressing a Bcl-2 transgene fail to rescue pre-B cell development, suggesting that the defect in B cell development in IRF4,8−/− mice is not due to a lack of survival signal. IRF4,8−/− pre-B cells display a high proliferation index that may indirectly inhibit the L chain rearrangement. However, forced cell cycle exit induced by IL-7 withdrawal fails to rescue the development of IRF4,8−/− pre-B cells, suggesting that cell cycle exit by itself is not sufficient to rescue the development of IRF4,8−/− pre-B cells and that IRF4,8 may directly regulate the activation of L chain loci. Using retroviral mediated gene transduction, we show that IRF4 and IRF8 function redundantly to promote pre-B cell maturation and the generation of IgM+ B cells. Molecular analysis indicates that IRF4, when expressed in IRF4,8−/− pre-B cells, induces κ germline transcription, enhances V(D)J rearrangement activity at the κ locus, and promotes L chain rearrangement and transcription. Chromatin immunoprecipitation assay further reveals that IRF4 expression leads to histone modifications and enhanced chromatin accessibility at the κ locus. Thus, IRF4,8 control pre-B cell development, at least in part, by promoting the activation of the κ locus.

Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation

“…49 Increased IRF4 expression was common to all 3 types of bortezomib-resistant MCL cells investigated here. IRF4 fulfills critical functions at several stages of B-cell development, 53,54 and is required for class-switch recombination, plasma-cell differentiation, and survival. 32,55 MM cells are highly dependent on IRF4.…”

Gene structure and transcription of IRF-1 and IRF-7 in the mandarin fish Siniperca chuatsi

“…IRF-2 was usually regarded as a transcriptional repressor, but it could also activate the transcription of several other genes (Vaughan et al, 1995;Xi et al, 1999). IRF-4 and IRF-8 govern dendritic cell subset development and their functional diversity, and promote immunoglobulin light chain locus activation in pre-B cell development (Tamura et al, 2005;Ma et al, 2006). IRF-3, IRF-5 and IRF-7 have been recognized as direct transducers in virus-mediated signaling (Barnes et al, 2002).…”

Interferon regulatory factor 4 regulates thymocyte differentiation by repressing Runx3 expression

“…Notably, it has been reported that IRF4-deficient mice have normal size thymi and show a normal distribution of thymic cell populations similar to WT controls [24]. The lack of a strong phenotype may be due to functional redundancy between IRF4 and other family members [37,38]. In fact, the IRF family includes at least ten members [19,20], and many other IRF family members have shown a similar express pattern in thymocytes as IRF4 (Supporting Information Fig.…”