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Transcription factor Etv6 controls functional differentiation of cross-presenting classical dendritic cells [ATAC-Seq]

ABSTRACT: An IRF8-dependent subset of classical dendritic cells (cDCs), termed DC1, effectively cross-primes CD8+ T cells and facilitates antitumor T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function. We report that like HSPC, cDCs express Etv6 but not its antagonist ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow reduced the generation of DC1-like cells in vitro and the differentiation of DC1 in vivo, including the loss of signature marker CD8a. Global expression and chromatin profiling of Etv6-deficient DCs revealed impaired lineage identity of DC1, including the reduction of cDC signature and upregulation of pDC signature. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and tumor-specific CD8+ T cell responses. These results identify Etv6 as a regulator of DC1 differentiation and functional fitness that indirectly facilitates T cell cross-priming and antitumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE106405 | GEO | 2018/08/03

REPOSITORIES: GEO

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Transcription factor Etv6 controls functional differentiation of cross-presenting classical dendritic cells [RNA-Seq]

Project description:An IRF8-dependent subset of classical dendritic cells (cDCs), termed DC1, effectively cross-primes CD8+ T cells and facilitates antitumor T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function. We report that like HSPC, cDCs express Etv6 but not its antagonist ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow reduced the generation of DC1-like cells in vitro and the differentiation of DC1 in vivo, including the loss of signature marker CD8a. Global expression and chromatin profiling of Etv6-deficient DCs revealed impaired lineage identity of DC1, including the reduction of cDC signature and upregulation of pDC signature. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and tumor-specific CD8+ T cell responses. These results identify Etv6 as a regulator of DC1 differentiation and functional fitness that indirectly facilitates T cell cross-priming and antitumor immunity.

2018-08-03 | GSE106406 | GEO

RNA-seq analysis of mouse cDC1 and cDC2 populations upon DC-SCRIPT depletion

Project description:The functional diversification of dendritic cells (DCs) is a key step in establishing protective immune responses. Despite the importance of this lineage diversity, its genetic basis is not fully understood. DC-SCRIPT (Zfp366) is a poorly known transcription factor expressed in conventional DCs (cDCs) and their committed bone marrow progenitors but not in plasmacytoid DCs (pDCs). We show that mice lacking DC-SCRIPT displayed substantially impaired development of IRF8-dependent conventional DC1 (cDC1), while cDC2 differentiated normally. The residual DC-SCRIPT-deficient cDC1s had impaired CD8+ T-cell cross-priming, which could be in part explained by the direct control of DC-SCRIPT on IL-12p40 production. Genome-wide mapping of DC-SCRIPT binding and gene expression analyses revealed a key role for DC-SCRIPT in maintaining cDC1 identity via the direct regulation of cDC1 signature genes, including Irf8. Our study reveals DC-SCRIPT to be a critical component of the gene regulatory program shaping the functional attributes of cDC1s.

2021-02-24 | GSE165125 | GEO

DC-SCRIPT (Zpf366) binding in cDC1 and cDC2 cells from wildtype and DC-SCRIPT knockout mice

2021-02-24 | GSE165138 | GEO

RNA-seq and CUT&Tag analysis of mouse cDC1 and cDC2 populations upon DC-SCRIPT depletion

2021-02-24 | GSE165361 | GEO

Influence of T and B lymphocytes on the antigen presentation capacities of splenic conventional dendritic cells

Project description:The goal of this project was to characterize DCs from lymphopenic mice, like RAG (recombination activated gene) deficient mice and to examine the influence of mature B and T cells on the antigen presenting ability of splenic cDCs. We demonstrate how cellular cross-talk can shape the character and function of cDCs. Lymphopenic conditions, where splenic cDCs have to develop and differentiate, drastically change their character and their ability to cross-present soluble antigen. In this approach we sorted out two populations (CD8?+ and CD8?-) of splenic dendritic cells (DCs) from untreated WT, and RAG2-/- C57Bl/6 mice. The age of mice was between 8-10 weeks. Further we isolated RNA and performed microarray analysis. Each DCs population was repeated twice.

2013-01-22 | E-GEOD-17989 | biostudies-arrayexpress

Extracellular vesicles (EV) from IFNγ-primed cardiosphere-derived cells (CDCs)

Project description:Characterization of proteins in extracellular vesicles (EV) from cardiosphere-derived cells (CDCs) of a clinically relevant pig model. Additionally, considering that priming stem cells with inflammatory stimuli may increase the therapeutic potential of released vesicles, here we studied the dynamic changes that take place in the EV from IFNγ-primed CDCs.

2020-05-15 | PXD016434 | Pride

RNA m6A-Ythdf1 in dendritic cells triggers anti-tumor immunity (ribo-seq and m6a-seq in GMDCs)

Project description:Emerging evidence emphasizes the important role of tumor neoantigen in generating the spontaneous antitumor immune response and predicting the clinical response to immunotherapies. Despite the presence of numerous neoantigens, complete tumor elimination rarely occurs in majority of patients due to failures in mounting a sufficient and lasting antitumor immunity. Here we show that the durable neoanitgen-specific immunity is regulated by a m6A-binding protein, Ythdf1. In contrast to wild-type mice, Ythdf1-deficient (Ythdf1-/-) mice generate more antigen-specific CD8+ T cell response for persistent tumor control. Loss of Ythdf1 in dendritic cell (DC) results in an enhanced cross-presentation of tumor antigen and cross-priming of CD8+ T cell in vivo. To confirm our observations, we performed Ribo-Seq to analyze the translational efficiency of genes in DCs and performed m6A-seq to locate the m6A sites.

2018-12-29 | GSE115105 | GEO

RNA m6A-Ythdf1 in dendritic cells triggers anti-tumor immunity (RNA-seq and RIP-seq in in GMDCs)

Project description:Emerging evidence emphasizes the important role of tumor neoantigen in generating the spontaneous antitumor immune response and predicting the clinical response to immunotherapies. Despite the presence of numerous neoantigens, complete tumor elimination rarely occurs in majority of patients due to failures in mounting a sufficient and lasting antitumor immunity. Here we show that the durable neoanitgen-specific immunity is regulated by a m6A-binding protein, Ythdf1. In contrast to wild-type mice, Ythdf1-deficient (Ythdf1-/-) mice generate more antigen-specific CD8+ T cell response for persistent tumor control. Loss of Ythdf1 in dendritic cell (DC) results in an enhanced cross-presentation of tumor antigen and cross-priming of CD8+ T cell in vivo. To confirm our observations, we performed RNA-Seq to analyze the transcriptional level of genes in DCs and performed RNA Immunoprecipitation (RIP-seq) to locate the binding sites of Ythdf1.

2018-12-29 | GSE106772 | GEO

RNA m6A-Ythdf1 in dendritic cells triggers anti-tumor immunity (MeRIP-Seq, RIP-Seq and Ribo-Seq in Flt3L-DCs)

2018-12-29 | GSE121933 | GEO

Gene expression profiling of mouse splenic Dendritic cells subsets

Project description:We describe a novel subset of CD8+ DCs in lymphoid organs of naïve mice characterized by expression of the CX3CR1 chemokine receptor. CX3CR1+CD8+ DCs lack hallmarks of classical CD8+ DCs, including IL12 secretion, the capacity to cross-present antigen and their developmental independence of the transcriptional factor BatF3. Gene expression profiling showed that CX3CR1+CD8+ DCs resemble CD8- cDCs. The microarray analysis further revealed a unique plasmacytoid DC (PDC) gene signature of CX3CR1+ CD8+ DCs. A PDC relationship of the cells is further supported by the fact that they harbor characteristic D-J immunoglobulin gene rearrangements and that development of CX3CR1+CD8+ DCs requires E2-2, the critical transcriptional regulator of PDCs. Thus, CX3CR1+ CD8+ DCs represent a unique DC subset, related to but distinct from PDCs. After collagenase D digestion, spleens from Cx3cr1gfp/+ C57BL/6 mice were enriched for CD11c+ cells by magnetic separation according to the manufacturer’s protocol (MiltenyiBiotec GmbH). Splenic CD11chi cells were isolated using the FACS ARIA high-speed sorter (Becton-Dickinson). Total RNA was extracted and subjected to gene expression profiling using the Mouse Genome 430.2 Affymetrix GeneChip

2010-07-28 | E-GEOD-23212 | biostudies-arrayexpress

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