TGF-β1 Accelerates Dendritic Cell Differentiation from Common Dendritic Cell Progenitors and Directs Subset Specification toward Conventional Dendritic Cells

Felker, Piritta; Seré, Kristin; Lin, Qiong; Becker, Christiane; Hristov, Mihail; Hieronymus, Thomas; Zenke, Martin

doi:10.4049/jimmunol.0903950

Cited by 52 publications

(72 citation statements)

References 67 publications

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“…In this way, ID3 and, perhaps, BCL11A autoregulation, provide homeostatic maintenance within pDC by buffering E2-2. Conversely, Id2 −/− mice display no loss of pDC (24), yet ID2 remains expressed (albeit at modest levels) in CDP but not in pDC (20,40); this leads us to speculate that within the CDP, BCL11A fortifies the default pathway by E2-2-mediated down-regulation of the ID2 repressor while concurrently driving MTG16 expression, thereby reducing ID2 activity at the protein level (41). For ID2 to rise to levels that would push CDPs to cDCs, it must downregulate E2-2, BCL11A, and the other default pathway genes that are increased during the commitment of MDP to CDP but not to monocytes (20).…”

Section: Discussionmentioning

confidence: 99%

“…ID2 and ID3, in particular, have documented roles in murine and human B-cell, T-cell, and pDC biology, and modulate the developmental potential of CDPs and CLPs (23)(24)(25)(26)(27)(28)(29)(30). Though both Id2 and Id3 are coexpressed in purified CDPs (40), only Id3 is detectable in CLPs (49), and notably, differential expression is maintained in the downstream cDC and pDC progeny where cDCs are strongly positive for Id2 but chiefly negative for Id3, and the opposite is true for pDC (40). We have uncovered a role for BCL11A in the transcriptional regulation of ID3, which calls to mind the related identification of ID2 as a target gene repressed by BCL11B (50), a highly similar paralogue of BCL11A essential for T-cell development (2).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dendritic cell fate is determined by BCL11A

Ippolito

Dekker

Wang

et al. 2014

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

109

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The plasmacytoid dendritic cell (pDC) is vital to the coordinated action of innate and adaptive immunity. pDC development has not been unequivocally traced, nor has its transcriptional regulatory network been fully clarified. Here we confirm an essential requirement for the BCL11A transcription factor in fetal pDC development, and demonstrate this lineage-specific requirement in the adult organism. Furthermore, we identify BCL11A gene targets and provide a molecular mechanism for its action in pDC commitment. Embryonic germ-line deletion of Bcl11a revealed an absolute cellular, molecular, and functional absence of pDCs in fetal mice. In adults, deletion of Bcl11a in hematopoietic stem cells resulted in perturbed yet continued generation of progenitors, loss of downstream pDC and B-cell lineages, and persisting myeloid, conventional dendritic, and T-cell lineages. Challenge with virus resulted in a marked reduction of antiviral response in conditionally deleted adults. Genome-wide analyses of BCL11A DNA binding and expression revealed that BCL11A regulates transcription of E2-2 and other pDC differentiation modulators, including ID2 and MTG16. Our results identify BCL11A as an essential, lineage-specific factor that regulates pDC development, supporting a model wherein differentiation into pDCs represents a primed "default" pathway for common dendritic cell progenitors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dendritic cell fate is determined by BCL11A

Ippolito

Dekker

Wang

et al. 2014

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

109

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“…The CDP is the natural candidate for this choice, since it has extinguished its ability to form alternate lineages, but still retains the ability to generate all DC subsets. Recent studies, as well as unpublished studies from our lab, have provided expression profile data for each sequential stage of DC differentiation in vivo including the CDP [116]. Strikingly, analysis of transcription factors expressed in CDPs reveals that a number of pDC factors, including E2-2, Bcl11a, and Runx2, are already expressed at moderate levels ( Figure 4).…”

Section: Gene Expression Analysis Of the Cdp Points To "Pdc-priming"mentioning

confidence: 99%

Transcription factor networks in dendritic cell development

Satpathy

Murphy

2011

Seminars in Immunology

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Dendritic cells (DCs) are a heterogeneous population within the mononuclear phagocyte system (MPS) that derive from bone marrow precursors. Commitment and specification of hematopoietic progenitors to the DC lineage is critical for the proper induction of both immunity and tolerance. This review summarizes the important cytokines and transcription factors required for differentiation of the DC lineage as well as further diversification into specific DC subsets. We highlight recent advances in the characterization of immediate DC precursors arising from the common myeloid progenitor (CMP). Particular emphasis is placed on the corresponding temporal expression of relevant factors involved in regulating developmental options.

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“…It was reported recently that treatment of hematopoietic progenitors with TGF-␤ shifts the differentiation of CDPs toward cDCs through the induction of instructive factors for cDC development and the inhibition of factors necessary for pDC development. 36 Considering that p15Ink4b is a known downstream target of TGF-␤ treatment, 37 our present observations suggest that p15Ink4b is one of the important effectors of TGF-␤ signaling that modulate cDC development. This is supported by our observations that the steady-state levels of splenic and BM CD8 Ϫ cDCs were also negatively affected by the deletion of p15Ink4b, whereas pDCs and CD8 ϩ cDC numbers were not.…”

Section: Discussionmentioning

confidence: 63%

The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells

Fares

Koller

Humeniuk

et al. 2012

Blood

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The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development. The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo-generated BMderived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation. Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses. (Blood. 2012;119(21):5005-5015) IntroductionIn acute myeloid leukemia (AML), one of the most common epigenetic abnormalities observed in patients is the transcriptional silencing of p15INK4b (Cdkn2b) by DNA hypermethylation. 1,2 Increased DNA methylation of the p15INK4b gene regulatory sequences has been reported in up to 80% of all patients suffering from AML, and in a high proportion of patients with other hematologic disorders, including myelodysplastic syndrome (MDS), and myeloproliferative neoplasms. 3,4 Clinical observations have established a strong correlation between the methylation levels of p15INK4b and poor prognosis in patients. Hypermethylation also provides a biomarker for the subsequent transformation and progression of the disease to a more aggressive phenotype. 3 The tumor-suppressor function of p15Ink4b for myeloid diseases was confirmed experimentally in an animal model with myeloidspecific deletion of the gene. These mice suffer from a mild form of myeloproliferative neoplasm resembling chronic myelomonocytic leukemia and are strongly predisposed to retrovirus-induced AML. 5 p15INK4b is a cyclin-dependent kinase inhibitor (CDKI) that binds and inhibits the activity of 2 cyclin-dependent kinases, CDK4 and CDK6. This inhibition leads to cell-cycle arrest during the early and mid-G 1 phase. 6 In accordance with its cell cycleinhibitory function, the expression levels of p15Ink4b are reported to be increased during the late maturation stages of myeloid progenitors associated with terminal differentiation into macrophages. 7 p15Ink4b has also been shown to play a role during early stages of hematopoiesis independently from its cell cycleinhibitory function. 8 During ea...

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TGF-β1 Accelerates Dendritic Cell Differentiation from Common Dendritic Cell Progenitors and Directs Subset Specification toward Conventional Dendritic Cells

Abstract: Material

Cited by 52 publications

References 67 publications

Dendritic cell fate is determined by BCL11A

Dendritic cell fate is determined by BCL11A

Transcription factor networks in dendritic cell development

The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells

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