IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development

Abstract

IRF-4,8 are two specialized members of the interferon regulatory factor (IRF) family that have been implicated in regulating immunoglobulin (Ig) light-chain gene transcription during B-lymphocyte development (Pongubala et al. 1992;Eisenbeis et al. 1995;Shaffer et al. 1997;Brass et al. 1999; Muljo and Schlissel 2002). They are more highly related to one another than to other IRFs and are selectively expressed in the lymphoid and myeloid lineages of the immune system (for review, see Taniguchi et al. 2001). IRF-4,8 bind very weakly to DNA-containing IRF sites, but are recruited to their binding sites via interactions with other transcription factors. In particular, the related Ets family transcription factors PU.1 and Spi-B have been shown to recruit IRF-4 or IRF-8 to Ets-IRF composite elements (EICE) in Ig 3Ј and enhancers (Pongubala et al. 1992;Eisenbeis et al. 1995;Brass et al. 1999;Escalante et al. 2002). These heterodimeric protein complexes have been implicated in the control of Ig light-chain gene transcription. PU.1 is required for early B-cell development and Spi-B is important for B-cell activation (Scott et al. 1994;Su et al. 1997). It remains to be determined whether PU.1/Spi-B regulate Ig light-chain gene expression during the pre-B-to-B transition. IRF-4 −/− mutant mice exhibit profound defects in B-and T-cell activation that are manifested in the failure to mount antibody, cytotoxic, or antitumor responses (Mittrucker et al. 1997;Rengarajan et al. 2002). IRF-8 −/− mutant mice are impaired in macrophage development, highly susceptible to viral infections, and manifest a chronic myelogenous leukemia-like syndrome (Holtschke et al. 1996). Loss of either IRF-4 or IRF-8 does not block the generation of B lymphocytes. Given their structural relatedness and similar molecular properties, we sought to examine whether they function redundantly to regulate Ig lightchain gene expression and the pre-B-to-B transition. (Fig. 1A). Strikingly, the double mutant mice lacked sIgM + peripheral B lymphocytes (Fig. 1B). In contrast, splenic T lymphocytes, (CD4 + or CD8 + ) were present in the double mutant mice, albeit with reduced numbers (Fig. 1C). We note that loss of IRF-4 and IRF-8 does not impair T-cell development in the thymus (data not shown). We next examined B-cell generation in the bone marrow. Immature IgM + B cells were absent in the IRF-4,8 −/− bone marrow (Fig. 1D). These results establish that the combined loss of IRF-4,8 causes a lineage-specific block to B-cell development. It should be noted that as is the case for IRF-8 −/− mice, there was an increase in the numbers of myeloid cells Fig. 2A). The levels of HSA expression on the mutant B220 + , CD43 + , BP-1 + , B-lineage cells were particularly high, suggesting that they represent transitional pre-B cells, which are a subset of fraction C cells in the nomenclature of Hardy et al. (1991). The disproportionate increase in the percentage fraction C cells in the IRF-4,8 −/− bone marrow ( Fig. 2A) was also reflected in a substantial increase in their a...

IRF-4 Suppresses BCR/ABL Transformation of Myeloid Cells in a DNA Binding-independent Manner

“…In addition, IRF-8 has overlapping functions with IRF-4 in early B cell development. Both proteins can interact with tran-scription factors PU.1 and E2A at the Ig and light chain enhancer regions (17) and both regulate Ikaros and Aiolos expression (18). Consistently, mice deficient in both IRF-4 and IRF-8 show a block in B cell development at the pre-B to immature B transition and display an accumulation of cycling pre B cells (19).…”

Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

“…32,48 Irf4 is a member of the interferon-regulatory factor family of transcription factors characterized by a specific DNA-binding domain and has the ability to either activate or repress the transcription of interferon-inducible genes. 18,31 Expression of Irf4 is restricted to cells of the immune system, including lymphocytes, dendritic cells and macrophages, in which it has been linked to a variety of functions, such as proliferation, apoptosis and differentiation.…”

“…33,34,49 Irf4 knockout mice have normal early B-cell development but profound reduction in serum immunoglobulin concentrations and show incapability to mount antibody responses because of a latestage blockage in peripheral B-cell maturation that leads to the absence of plasma cells, plasmablasts and classswitched B cells. 30,35 Recently, the Irf4 gene has been demonstrated to have a biphasic expression pattern: it is expressed in immature B cells in the bone marrow, 48 absent from proliferating germinal center centroblasts and then re-expressed in a subpopulation of centrocytes in the germinal center and in plasma cells. 50 Extending these studies, the evidences provided here introduce the notion that natural genetic variation at the Irf4 gene impacts in its expression levels, being a major factor in the quantitative control of terminal B-cell differentiation and, consequently of natural IgM serum concentration.…”

Somatic stem cells and the origin of cancer

“…Alternatively, CLPs can differentiate to T-cells through Notch1 activation, which is negatively regulated by PAX5 [166][167][168] . Recent studies have shown the role of FOXP1 in the transition of pro-B cells to pre-B cells, a step which is also controlled by IRF4/MUM1 and IRF8 169,170 . More differentiated B-cells are also tightly programmed by transcription factors.…”