The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2

Scott, Charlotte; Soen, Bieke; Martens, Liesbet; Skrypek, Nicolas; Saelens, Wouter; Taminau, Joachim; Blancke, Gillian; Isterdael, Gert Van; Huylebroeck, Danny; Haigh, Jody J.; Saeys, Yvan; Guilliams, Martin; Lambrecht, Bart N.; Berx, Geert

doi:10.1084/jem.20151715

Cited by 124 publications

(146 citation statements)

References 51 publications

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“…The positive feedback mechanism of TCF4 regulation helps explain essential features of the pDC vs cDC lineage choice, including its apparent cell-intrinsic nature; resolution from a TCF4-intermediate progenitor state into TCF4-expressing pDCs and Id2-expressing cDCs; and enhanced DC1 development at the expense of pDCs upon the net reduction of E protein activity (Ghosh et al, 2014; Scott et al, 2016). Similar mechanisms involving E proteins and their antagonists are likely operational in other immune cell lineages such as T and B lymphocytes, as well as in other tissues such as the brain.…”

Section: Discussionmentioning

confidence: 99%

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

et al. 2017

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Summary The cell fate decision between interferon-producing plasmacytoid DC (pDC) and antigen-presenting classical DC (cDC) is controlled by the E protein transcription factor TCF4 (E2-2). We report that TCF4 comprises two transcriptional isoforms, both of which are required for optimal pDC development in vitro. The long Tcf4 isoform is expressed specifically in pDCs, and its deletion in mice impaired pDCs development and led to the expansion of non-canonical CD8+ cDCs. The expression of Tcf4 commenced in progenitors and was further upregulated in pDCs, correlating with stage-specific activity of multiple enhancer elements. A conserved enhancer downstream of Tcf4 was required for its upregulation during pDC differentiation, revealing a positive feedback loop. The expression of Tcf4 and the resulting pDC differentiation were selectively sensitive to the inhibition of enhancer-binding BET protein activity. Thus, lineage-specifying function of E proteins is facilitated by lineage-specific isoform expression and by BET-dependent feedback regulation through distal regulatory elements.

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Section: Discussionmentioning

confidence: 99%

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

et al. 2017

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“…The transcription factors that are known to influence DC development are IRF8, IRF4, PU.1, Id2, Batf3, E2-2, Nfil3, Notch2, Bcl6, and Zeb2 (17,27,28). An intrinsic requirement for each of these factors has been established through the examination of lineage-specific conditional deletion in vivo, analysis of mixed BM chimeras, or defective development in Flt3L-treated BM cultures.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of transcription factor RelB perturbs myeloid and DC development by hematopoietic-extrinsic mechanisms

Briseño

Gargaro

Durai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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RelB is an NF-κB family transcription factor activated in the noncanonical pathway downstream of NF-κB-inducing kinase (NIK) and TNF receptor family members including lymphotoxin-β receptor (LTβR) and CD40. Early analysis suggested that RelB is required for classical dendritic cell (cDC) development based on a severe reduction of cDCs in Relb −/− mice associated with profound myeloid expansion and perturbations in B and T cells. Subsequent analysis of radiation chimeras generated from wild-type and Relb −/− bone marrow showed that RelB exerts cell-extrinsic actions on some lineages, but it has remained unclear whether the impact of RelB on cDC development is cellintrinsic or -extrinsic. Here, we reevaluated the role of RelB in cDC and myeloid development using a series of radiation chimeras. We found that there was no cell-intrinsic requirement for RelB for development of most cDC subsets, except for the Notch2-and LTβR-dependent subset of splenic CD4 + cDC2s. These results identify a relatively restricted role of RelB in DC development. Moreover, the myeloid expansion in Relb −/− mice resulted from hematopoieticextrinsic actions of RelB. This result suggests that there is an unrecognized but critical role for RelB within the nonhematopoietic niche that controls normal myelopoiesis.

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“…The first model of specific pDC deficiency was conditional deletion of Tcf4 , which encodes the factor E2-2, with Itgax-cre (Cisse et al, 2008). Recently, conditional deletion of the transcription factor Zeb2 using Itgax-cre also demonstrated selective pDC deficiency (Scott et al, 2016). Table 3 provides a summary of the transcription factor knockout mice useful for the study of DCs.…”

Section: Mouse Models For Studying Dendritic Cellsmentioning

confidence: 99%

Functions of Murine Dendritic Cells

2016

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Dendritic cells (DCs) play critical roles in activating innate immune cells and initiating adaptive immune responses. The functions of DCs were originally obscured by their overlap with other mononuclear phagocytes, but new mouse models have allowed for the selective ablation of subsets of DCs and have helped to identify their non-redundant roles in the immune system. These tools have elucidated the functions of DCs in host defense against pathogens, autoimmunity, and cancer. This review will describe the mouse models generated to interrogate the role of DCs, and will discuss how their use has progressively clarified our understanding of the unique functions of DC subsets.

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The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2

Abstract: Lambrecht et al. show that the transcription factor Zeb2 regulates commitment toward both the pDC and cDC2 lineages by repressing Id2.

Cited by 124 publications

References 51 publications

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

Isoform-Specific Expression and Feedback Regulation of E Protein TCF4 Control Dendritic Cell Lineage Specification

Deficiency of transcription factor RelB perturbs myeloid and DC development by hematopoietic-extrinsic mechanisms

Functions of Murine Dendritic Cells

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