Ikaros has a crucial role in regulation of B cell receptor signaling

Nera, Kalle‐Pekka; Alinikula, Jukka; Terho, Perttu; Narvi, Elli; Törnquist, Kid; Kurosaki, Tomohiro; Buerstedde, Jean-Marie; Lassila, O.

doi:10.1002/eji.200535418

Cited by 36 publications

(54 citation statements)

References 50 publications

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“…For analysis of Pax5 protein expression, lysates from 3 Â 10 6 of WT, BCL6 À/À , BCL6 À/À /BCL6, BCL6 À/À /PAX5 cell lines were subjected to immunoprecipitation as previously described [4,35].…”

Section: Metabolic Labeling Immunoprecipitation and Western Blot Anamentioning

confidence: 99%

“…DT40 is a chicken bursa-derived cell line, which has a follicular B-cell gene expression program [29] and has been used to characterize Ig gene diversification [30], BCR signaling pathways [31,32] as well as the function of transcription factors regulating B-cell development [4,[33][34][35][36]. Therefore, we generated a BCL6 À/À DT40 B-cell line and dissected the transcription factor network underlying B-cell to plasma cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

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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: Metabolic Labeling Immunoprecipitation and Western Blot Anamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…The cDNA from 1 3 10 5 cell equivalent, which was prepared as indicated in Nera et al (2006), was amplified with primers Pax5-f 5 0 -GTCAGCCACGGCTGCGTCAGCAAAATAC-3 0 and Pax5-r 5 0 -GGCTGCTGCACCTTTGTCCGTATGAT-3 0 . A PCR reaction with the chicken b-actin-specific primers b1-f 5 0 -GTGCTGTGTTC CCATCTATCGT-3 0 and b1-r 5 0 -TGGACAATGGAGGGTCCGGATT-3 0 was used as a positive control.…”

Section: Rt-pcr Analysismentioning

confidence: 99%

Loss of Pax5 Promotes Plasma Cell Differentiation

et al. 2006

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Pax5 is indispensable for the commitment of early lymphoid progenitors to the B cell lineage as well as for the development of B cells. To better understand the functional importance of Pax5 at the later stages of B cell differentiation, we established a Pax5-deficient DT40 B cell line. The Pax5(-/-) cells exhibited slower growth, decreased surface IgM expression, and total loss of B cell receptor signaling. Moreover, the expression of the plasma cell-characteristic transcription factors Blimp-1 and XBP-1 were significantly upregulated and the expression of Bcl-6 diminished in the Pax5(-/-) cells, and this alteration was normalized by restored Pax5 expression. The Pax5-deficient cells further manifested substantially elevated secretion of IgM into the supernatant, another characteristic of plasma cells. These results indicate that downregulation of Pax5 function promotes the plasma cell differentiation of B cells.

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“…Ikaros is expressed throughout the B-cell development, but Ikarosdeficient mice lack B cells and all B-cell progenitors (Wang et al, 1996). Nonetheless, Ikaros-deficient DT40 cells are viable and exhibit a B-cell receptor (BCR) signalling defect (Nera et al, 2006a) thus revealing the importance of Ikaros in the regulation of B-cell function. Moreover, DT40 cells deficient in other Ikaros family member, Helios, are characterised with the hyper BCR signalling phenotype, suggesting that the concerted action of both Ikaros and Helios balances the strength of BCR signalling in B cells.…”

Section: Aid Expression and Abolished Ig Gene Conversionmentioning

confidence: 99%

Bursa of Fabricius

Mustonen

Alinikula

Lassila

et al. 2010

Encyclopedia of Life Sciences

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The bursa of Fabricius plays a central role in the development of the antibody‐producing B‐lymphocyte lineage in birds. It consists of more than 10 000 follicles surrounded by connective tissue. These follicles provide an appropriate microenvironment for generating a primary repertoire of antibodies. Immunoglobulin gene diversification is achieved by gene conversion and is antigen independent. Follicular B cells undergo very rapid cell division while expressing several genes also expressed in proliferating germinal centre B cells, such as AID , UNG , Pax5 and Bcl6 . Bursal B cell line DT40 provides a unique model system for gene‐targeting studies clarifying the B‐cell development, function and Ig diversification. Key Concepts: Bursa of Fabricius is the primary site for B‐cell development and antibody repertoire formation in birds. Antibody diversification in the bursa of Fabricius is antigen independent and occurs mostly by Ig gene conversion. Bursal derived DT40 B cell line provides a reverse genetic model to study molecular function of B cells.

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Ikaros has a crucial role in regulation of B cell receptor signaling

Cited by 36 publications

References 50 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

Loss of Pax5 Promotes Plasma Cell Differentiation

Bursa of Fabricius

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