Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination

Klein, Ulf; Casola, Stefano; Cattoretti, Giorgio; Shen, Qiong; Lia, Marie; Mo, Tongwei; Ludwig, Thomas; Rajewsky, Klaus; Dalla‐Favera, Riccardo

doi:10.1038/ni1357

Cited by 681 publications

(743 citation statements)

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“…We did not observe any binding of Bcl6 to the MITF gene, suggesting an indirect mechanism for Bcl6-mediated regulation of MITF expression. Interestingly, Bcl6 also bound to the IRF4 gene, an important regulator of PRDM1 and plasma cell differentiation [44,45]. Bcl6-specific enrichment peaks were observed in the region of the first $3000 bp from the TSS with the peak maxima occurring in the first, third and fourth introns (Fig.…”

Section: Relative Expressionmentioning

confidence: 91%

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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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Section: Relative Expressionmentioning

confidence: 91%

“…3), raising a possibility that the prominent mechanism by which Bcl6 regulates PRDM1 is not through direct DNA binding. Therefore, we searched for other Bcl6 regulated genes that have been reported to regulate PRDM1 or plasma cell differentiation, such as BACH2 [40][41][42], MITF [43], IRF4 [44,45].…”

Section: Bcl6 Binds Directly To Bach2 Ung and Irf4mentioning

confidence: 99%

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

et al. 2011

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“…OBF1 and Aiolos are crucial for the transition of pre-B cells to immature B cells expressing BCR, as well as for the mobilization of immature B-cells from bone marrow to the spleen, whereas NF-κB activation has essential roles in the transition of immature to mature B-cells [171][172][173] . Additionally, BCL6, IRF4, BLIMP1, XBP1 and PAX5 are involved in the terminal differentiation of B-cells into plasma cells [174][175][176][177][178][179][180][181][182] .…”

Section: Do Lymphoid Malignancies Arise From Mutations That Deregulatmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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“…Th us, signalling and transcriptional programs that determine B mem cell fate are still unknown. Similarly, it remains unclear what determines lineage choice by the affi nity-selected GC B cells to become LLPCs, although transcriptional regulators such as Blimp-1 and Irf4 are known to be essential for overall plasma cell diff erentiation 23,24 .…”

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confidence: 99%

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

et al. 2011

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In response to T cell-dependent antigens, B cells proliferate extensively to form germinal centres (GC), and then differentiate into memory B (B mem ) cells or long-lived plasma cells (LLPCs) by largely unknown mechanisms. Here we show a new culture system in which mouse na ï ve B cells undergo massive expansion and isotype switching, and generate GC-phenotype B (iGB) cells. The iGB cells expressing IgG1 or IgM / D, but not IgE, differentiate into B mem cells in vivo after adoptive transfer and can elicit rapid immune responses with the help of cognate T cells. Secondary culture with IL-21 maintains the proliferation of the iGB cells, while shifting their in vivo developmental fate from B mem cells to LLPCs, an outcome that can be reversed by withdrawal of IL-21 in tertiary cultures. Thus, this system enables in vitro manipulation of B-cell fate, into either B mem cells or LLPCs, and will facilitate dissection of GC-B cell differentiation programs.

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Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination

Cited by 681 publications

References 53 publications

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

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

Somatic stem cells and the origin of cancer

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

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