Insight into lymphoid development by gene expression profiling of avian B�cells

Koskela, Kari; Kohonen, Pekka; Nieminen, Pia; Buerstedde, Jean-Marie; Lassila, O.

doi:10.1007/s00251-003-0592-7

Cited by 35 publications

(25 citation statements)

References 55 publications

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“…DT40 cells are derived from an avian leucosis virus-induced bursal lymphoma, which appears to be arrested at the bursal B cell stage of the development (Buerstedde et al, 1990;Kim et al, 1990), as the gene expression profile of DT40 cells is rather similar to that of bursal B cells (Koskela et al, 2003). The DT40 cell line possesses a homologous recombination activity and integrates gene constructs targeted to virtually any gene loci at high ratios (Buerstedde and Takeda, 1991), thus allowing easy disruption of genes for experimental purposes.…”

Section: Bursal Dt40 Cell Line As a Model To Study B-cell Function Anmentioning

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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Section: Bursal Dt40 Cell Line As a Model To Study B-cell Function Anmentioning

confidence: 99%

Bursa of Fabricius

Mustonen

Alinikula

Lassila

et al. 2010

Encyclopedia of Life Sciences

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“…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%

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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“…To the resulting phenotypes, the transcription profiles of wildtype and mutant cells need to be analyzed. Micro-array analysis is able to measure the transcription levels of thousands of genes and first results using filter-or chip-based micro-arrays have been reported (Neiman et al, 2001;Koskela et al, 2003). Nevertheless, the cDNA inserts used for the micro-arrays were not completely sequenced thus complicating the assignment of signals to defined transcripts.…”

Section: Gene Expression Profilingmentioning

confidence: 99%