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Batf3 maintains Irf8 autoactivation for commitment of a novel clonogenic progenitor of CD8+DCs

ABSTRACT: The transcription factors Batf3 and IRF8 are required for development of CD8α+ conventional dendritic cells (cDCs), but the basis for their actions was unclear. Here, we identify two novel Zbtb46+ progenitors that separately generate CD8α+ and CD4+ cDCs and arise directly from the common DC progenitor (CDP). Irf8 expression in the CDP depends on prior PU.1-dependent autoactivation, and specification of pre-CD8 DC progenitors requires IRF8 but not Batf3. However, upon pre-CD8 DC specification, Irf8 autoactivation becomes Batf3-dependent at a CD8α+ cDC-specific enhancer containing multiple AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3-/- mice that specify toward pre-CD8 DCs fail to complete CD8α+ cDC development due to decay of Irf8 autoactivation, and divert to the CD4+ cDC lineage. Examination of histone modifications (H3K27ac and H3K4me1) and 2 transcription factors (Batf3 and Irf8) and the p300 co-factor binding in 3 different dendritic cell subsets

ORGANISM(S): Mus musculus

SUBMITTER: Gary Grajales-Reyes

PROVIDER: E-GEOD-66899 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Batf3 maintains Irf8 autoactivation for commitment of a novel clonogenic progenitor of CD8+DCs

Project description:The transcription factors Batf3 and IRF8 are required for development of CD8α+ conventional dendritic cells (cDCs), but the basis for their actions was unclear. Here, we identify two novel Zbtb46+ progenitors that separately generate CD8α+ and CD4+ cDCs and arise directly from the common DC progenitor (CDP). Irf8 expression in the CDP depends on prior PU.1-dependent autoactivation, and specification of pre-CD8 DC progenitors requires IRF8 but not Batf3. However, upon pre-CD8 DC specification, Irf8 autoactivation becomes Batf3-dependent at a CD8α+ cDC-specific enhancer containing multiple AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3-/- mice that specify toward pre-CD8 DCs fail to complete CD8α+ cDC development due to decay of Irf8 autoactivation, and divert to the CD4+ cDC lineage.

2015-06-08 | GSE66899 | GEO

Microarray analysis of WT ESAM+ and ESAM- cDC subsets

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2013-06-01 | E-GEOD-45679 | biostudies-arrayexpress

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2013-12-14 | E-GEOD-53312 | biostudies-arrayexpress

Microarray analysis of committed cDC progenitors

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2015-06-08 | E-GEOD-66565 | biostudies-arrayexpress

L-Myc expression by dendritic cells is required for optimal T-cell priming

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2013-12-14 | E-GEOD-53311 | biostudies-arrayexpress

L-Myc expression by dendritic cells is required for optimal T-cell priming

2013-12-14 | GSE53311 | GEO

Notch signaling facilitates in vitro generation of cross-presenting classical dendritic cells

Project description:The IRF8-dependent subset of classical dendritic cells (cDC), termed cDC1, is important for cross-priming cytotoxic T cell responses against pathogens and tumors. Culture of hematopoietic progenitors with DC growth factor Flt3 ligand (Flt3L) yields very few cDC1 (in humans) or only immature "cDC1-like" cells (in the mouse). We report that OP9 stromal cells expressing Notch ligand Delta-like 1 (OP9-DL1) optimize Flt3L-driven development of cDC1 from murine immortalized progenitors and primary bone marrow cells. Co-culture with OP9-DL1 induced IRF8-dependent cDC1 with the phenotype (CD103+ Dec205+ CD8α+) and expression profile resembling ex vivo cDC1. OP9-DL1-induced cDC1 showed preferential migration towards Ccr7 ligands in vitro and superior T cell cross-priming and antitumor vaccination in vivo. Co-culture with OP9-DL1 also greatly increased the yield of IRF8-dependent CD141+ cDC1 from human bone marrow progenitors cultured with Flt3L. Thus, Notch signaling optimizes cDC generation in vitro and yields authentic cDC1 for functional studies and therapeutic applications.

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Single cell RNA sequencing of small intestinal dendritic cells from C57BL/6, RORgt-/- and RORgt-Cre x Ltb-flox mice

Project description:Cryptopatches (CP) and isolated lymphoid follicles (ILF) are evolutionary ancient lymphoid structures found in the intestines of all vertebrates. These structures are demarcated by a poorly characterised subset of mononuclear phagocytes (MPh), called CP/ILF-associated (CIA)-MPh. We could demonstrate that CIA-MPh derive from a pre-DC from the bone marrow and thus are boafide dendritic cells. We called these newly identified cDC cells : cryptopatch and ILF associated dendritic cells (CIA-DC). To obtain unbiased insights into how CIA-DC are integrated into the intestinal cDC landscape, we performed single cell RNA-sequencing (scRNA-seq) of purified CD45+ CD64- I-A/I-E+ CD11chigh cells from C57BL/6 mice using the 10X Genomics droplet-based technology. Finally, to study the role of ILC3 in the final differentiation of CIA-DC, we performed single cell RNA-sequencing (scRNA-seq) of cDC from Rorc(γt)-/- and Ltb∆ILC3,T mice, using the 10X Genomics droplet-based technology.

2020-11-24 | E-MTAB-9522 | biostudies-arrayexpress

Cis-regulation between Irf8 enhancers during cDC1 development (ATAC-Seq)

Project description:Type 1 classical dendritic cells (cDC1s) development requires the transcription factor IRF8, and IRF8 mutations cause severe combined immunodeficiency, including disseminated bacille Calmette-Guérin (BCG) disease. IRF8 regulated enhancers are required for Irf8 expression in early DC progenitors and mature cDC1s. The E-protein-dependent +41 kb enhancer gains accessibility and activates transcription in common DC progenitors (CDPs), and its depletion abrogated pre-cDC1s specification. The Batf3-dependent +32 kb enhancer gains accessibility and activates transcription in pre-cDC1 progenitors, and its depletion impaired cDC1 maturation. The +32 kb Irf8 enhancer locus bears an enhancer transcript, and the production of enhancer RNA (eRNA) Gm39266 is dependent on +41 kb Irf8 enhancer. It was unclear whether the +32 kb and +41 kb enhancers act independently or cooperate to regulate Irf8 expression. We dissected the mechanisms using +32/+41 compound heterozygous mice, and found that while the +41 kb enhancer suffices for pre-cDC1 progenitor specification, the +32 kb and +41 kb enhancers must reside on one allele to support cDC1 maturation. The +41 kb enhancer cis-regulates chromatin accessibility and BATF3 binding at +32 kb enhancer, independent of eRNA Gm39266 transcripts or transcription across +32 kb Irf8 enhancer.

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