Blimp-1-Dependent Repression of <i>Pax-5</i> Is Required for Differentiation of B Cells to Immunoglobulin M-Secreting Plasma Cells

Lin, Kuo‐I; Angelin-Duclos, Cristina; Kuo, Tracy C.; Calame, Kathryn

doi:10.1128/mcb.22.13.4771-4780.2002

Cited by 407 publications

(364 citation statements)

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“…Innate immune factors such as IL2 can induce the expression of Prdm1; Prdm1 represses IL2 expression in turn and initiates leukocyte development in mouse [60]. Perhaps Prdm1a play the same role in the immune system of fish as its homologues in mammal to induce development of B, T and NK cells [2,3,5,[8][9][10][11][12][13][14][15][16][17].…”

Section: Discussionmentioning

confidence: 99%

“…The repression activity of Prdm1 is needed for development and maturation of lymphoid cells in the mammal [2,3,5,[8][9][10][11][12][13][14][15][16][17]. Mammal Prdm1 inhibits the expression of genes such as IL-2, c-Fos, ifng, tbx21 and bcl6 [60,61].…”

Section: Discussionmentioning

confidence: 99%

“…Prdm1 was first described as a protein binding to the beta-interferon promoter and repressing beta-interferon expression [1], and later was identified as a protein which being expressed upon differentiation of B lymphocytes to plasma cells and importantly, playing major role in activation of mature B cells and differentiation of B cells into plasma cells [2][3][4][5][6][7]. Prdm1-induced maturation of lymphocytes is correlated with the ability of Prdm1 to repress numbers of genes critical for mature B cell identity and cellular proliferation [5,[8][9][10][11][12][13]. Prdm1 is also needed for the activation of T cells [14][15][16][17][18], the differentiation of myeloid lineage [19] and the maturation of nature killer (NK) cells [20].…”

Section: Introductionmentioning

confidence: 99%

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Identification and expression profiles of prdm1 in medaka Oryzias latipes

et al. 2013

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Mouse Prdm1, also known as Blimp1, plays important roles in maturation and survival of lymphoid cells, as well as in organogenesis of muscle, limb, sensor organs and primordial germ cells. The homologues of mouse prdm1 have been identified in a diverse of animals including zebrafish and fugu. Here, we report the identification and expression profiles of two homologues of prdm1, namely prdm1a and prdm1b in medaka, Oryzias latipes. The transcripts of prdm1a and prdm1b were detectable in all the tissues including immune organs such as gill, spleen, kidney, liver and intestine that we have checked on. The transcripts of prdm1a could be detected in the embryonic shield at mid-gastrula stage and later in the somite, eye, otic vesicle, branchial arches, fin, intestine and cloaca during embryogenesis using in situ hybridization. Moreover, the expression of prdm1a in the liver of both medaka and zebrafish could be up-regulated by the immune stimuli including lipopolysaccharide, polyI:C and the grass carp reovirus, similarly to the up-regulation of IL1B. These results indicate that Prdm1a may play important roles in embryogenesis and also in immune response in fish.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and expression profiles of prdm1 in medaka Oryzias latipes

et al. 2013

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“…The suppression of Pax5 and Bcl6 expression by Blimp-1 [25,62] is most likely a secondary effect ensuring the irreversible nature of plasma cell differentiation. After successive affinity maturation, the increased receptor affinity for the antigen and the subsequent signaling leading to degradation of Bcl6 protein [5] could provide a trigger for relief of the suppression of IRF4 and PRDM1 directly and through mechanisms involving Bach2 and MITF.…”

Section: Discussionmentioning

confidence: 99%

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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The transcription factor Bcl6 regulates germinal center formation and differentiation of B cells into high-affinity antibody-producing plasma cells. The direct double-negative regulatory circuit between Bcl6 and Blimp-1 is well established. We now reveal alternative mechanisms for Bcl6-mediated regulation of B-cell differentiation to plasma cells and show with DT40 cells that Bcl6 directly promotes the expression of Bach2, a known suppressor of Blimp-1. Moreover, Bcl6 suppresses Blimp-1 expression through direct binding to the IRF4 gene, as well as by promoting the expression of MITF, a known suppressor of IRF4. We also provide evidence that Bcl6 is needed for the expression of AID and UNG, the indispensable proteins for somatic hypermutation and class-switch recombination, and UNG appears to be a direct Bcl6 target. Our findings reveal a complex regulatory network in which Bcl6 acts as a key element dictating the transition of DT40 B cells to plasma cells. Supporting Information available online See accompanying Commentary by Tarlinton IntroductionThe transition of activated B cells into high-affinity antibodyproducing plasmablasts, plasma cells and memory B cells in the germinal centers (GCs) is a biologically unique process involving rapid B-cell proliferation coupled with a high rate of mutation in the variable regions of immunoglobulin (Ig) genes. Considering that the majority of B-cell lymphomas originate from the GC B cells [1], a comprehensive understanding of the transcriptional regulation controlling the transition of B cells to plasma cells is essential. The transcription factors Blimp-1, Xbp-1 and IRF4 have been identified to be critical regulators promoting the Ig secretion and plasma cell phenotype, whereas Pax5, Bcl6, MITF and Bach2 are the known inhibitors of plasma cell development [2].Previous studies have shown that the downregulation of B-cell identity factor Pax5 occurs before the induction of the plasma cell transcription program [3,4], and that the loss of Pax5 expression [4] leads to the downregulation of BCL6. Furthermore, B-cell receptor (BCR) signaling of sufficient affinity leads to rapid phosphorylation and degradation of Bcl6 protein [5], while Bcl6 can also be functionally inactivated by acetylation [6]. These features of Bcl6 make it a prominent molecular trigger that controls the plasma cell differentiation.The transcription factor Bcl6 has been demonstrated to be essential for GC B-cell development, as Bcl6 knockout mice fail to develop GCs and do not produce high-affinity antibodies [7][8][9]. Recent work revealed that Bcl6 is also needed for follicular T helper cell development [10][11][12]. Analyses of Bcl6 target genes in B cells indicate that suppression of apoptosis and cell cycle arrest responses occur through p53, p21 and CHEK1 and Bcl6 also regulates DNA damage responses by controlling ATR [13][14][15][16]. Thus, Bcl6 appears to function as a factor permitting rapid B-cell 2404proliferation and tolerance for DNA damage in GCs. Bcl6 also represses genes that are involve...

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“…MYC [10], MHC2TA [11], PAX5 [12] and many other genes [13] have recently been shown to be targets of PRDM1-dependent repression during PC differentiation. However, very few studies have been performed to elucidate how the PRDM1 gene is transcriptionally regulated.…”

Section: Introductionmentioning

confidence: 99%

Transcription of PRDM1, the master regulator for plasma cell differentiation, depends on an SP1/SP3/EGR‐1 GC‐box

et al. 2008

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The positive regulatory domain containing 1, encoded by the PRDM1 gene, is a transcriptional repressor considered as a master regulator that is required and sufficient for plasma cell differentiation. In the present study we have performed sequence analysis of the upstream region of the human PRDM1 gene to detect the minimal promoter region necessary for PRDM1 gene transcription. This region comprises the region upstream of the initiation site, as well as the first exon. Collectively, deletion and mutation analysis in conjunction with luciferase reporter assays, EMSA and supershift assays identified a phylogenetically conserved GC-box as an essential element for PRDM1 expression. This GC-box element matches to a binding site for multiple transcription factors such as SP1 and SP3 isoforms as well as early growth response 1. Chromatin immunoprecipitation assays confirmed the in vivo binding capability of these factors to the human PRDM1 promoter. These studies together characterize for the first time the basal activity of the human PRDM1 promoter, through which several factors, including SP1, SP3 and early growth response 1, modulate its expression through a conserved GC-box.Key words: B cell differentiation Á Human Á PRDM1 Á Transcription factors Supporting Information available online IntroductionPlasma cells (PC), i.e. terminally differentiated B lymphocytes in a post-mitotic state, are immunoglobulin (Ig)-secreting cells playing a central role in the antigen-specific immune response. The plasmacytic differentiation process is regulated by the "turn off" and "turn on" of many specific transcription factors (TF), which are now starting to be elucidated [1][2][3][4]. One of these, the human positive regulatory domain containing 1 with zinc-finger domain (PRDM1), is considered as a key factor that promotes the nonproliferative and differentiated stage of PC [4, 5]. The PRDM1 factor was initially identified as a 98-kDa DNA-binding protein that contains five zinc-finger domains and acts as a repressor of interferon-b gene expression [6]. Its murine homolog, initially called B lymphocyte-induced maturation protein-1 (Blimp-1), was isolated as a mouse gene that is induced during B lymphocyte maturation [7]. It is expressed at high levels only in late B cells and PC, and the ectopic overexpression of PRDM1 is sufficient to drive B lymphocytes to differentiate into PC [7]. Moreover, its expression is required for the formation of Ig-secreting cells [8] and for the maintenance of long-lived PC in bone marrow [9].MYC Here we have defined the minimal promoter for human PRDM1 transcription enclosing a GC-rich element necessary for basal transcription. Moreover, this GC-rich element contains an SP1/early growth response 1 (EGR-1) overlapping binding site to which the regulatory factors SP1, SP3 and EGR-1 can bind, which activate the PRDM1 transcription. Results and discussionStructure of the 5 0 -flanking region and initiation sites of the human PRDM1 gene To obtain insight into the regulation of the human PRDM1 gene and b...

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Blimp-1-Dependent Repression of Pax-5 Is Required for Differentiation of B Cells to Immunoglobulin M-Secreting Plasma Cells

Cited by 407 publications

References 39 publications

Identification and expression profiles of prdm1 in medaka Oryzias latipes

Identification and expression profiles of prdm1 in medaka Oryzias latipes

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

Transcription of PRDM1, the master regulator for plasma cell differentiation, depends on an SP1/SP3/EGR‐1 GC‐box

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