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ZDC (Zbtb46, Btbd4) knockout classical dendritic cells

ABSTRACT: Classical dendritic cells (cDCs) process and present antigens to T cells. Under steady-state conditions, antigen presentation by cDCs induces tolerance. In contrast, during infection or inflammation, cDCs become activated, express higher levels of cell surface MHC molecules, and induce strong adaptive immune responses. We recently identified a cDC-restricted zinc finger transcription factor, zDC, that is not expressed by other immune cell populations, including pDCs, monocytes, or macrophages. Here we define the zDC consensus DNA binding motif and the genes regulated by zDC using chromatin immunoprecipitation and deep sequencing. By deleting zDC from the mouse genome, we show that zDC is primarily a negative regulator of cDC gene expression. zDC deficiency alters the cDC subset composition in the spleen in favor of CD8+ DCs, upregulates activation pathways in steady state cDCs including elevated MHC II expression, and enhances cDC production of VEGF leading to increased vascularization of skin-draining lymph nodes. Consistent with these observations, zDC protein expression is rapidly downregulated after TLR ligation. Thus, zDC is a TLR-responsive cDC-specific transcriptional repressor that is in part responsible for preventing cDC maturation in the steady state.

ORGANISM(S): Mus musculus

PROVIDER: GSE37995 | GEO | 2012/07/16

SECONDARY ACCESSION(S): PRJNA166879

REPOSITORIES: GEO

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zDC (Zbtb46, Btbd4) knockout classical dendritic cells

Project description:Classical dendritic cells (cDCs) process and present antigens to T cells. Under steady-state conditions, antigen presentation by cDCs induces tolerance. In contrast, during infection or inflammation, cDCs become activated, express higher levels of cell surface MHC molecules, and induce strong adaptive immune responses. We recently identified a cDC-restricted zinc finger transcription factor, zDC, that is not expressed by other immune cell populations, including pDCs, monocytes, or macrophages. Here we define the zDC consensus DNA binding motif and the genes regulated by zDC using chromatin immunoprecipitation and deep sequencing. By deleting zDC from the mouse genome, we show that zDC is primarily a negative regulator of cDC gene expression. zDC deficiency alters the cDC subset composition in the spleen in favor of CD8+ DCs, upregulates activation pathways in steady state cDCs including elevated MHC II expression, and enhances cDC production of VEGF leading to increased vascularization of skin-draining lymph nodes. Consistent with these observations, zDC protein expression is rapidly downregulated after TLR ligation. Thus, zDC is a TLR-responsive cDC-specific transcriptional repressor that is in part responsible for preventing cDC maturation in the steady state. Splenic classical dendritic cells from mice lacking the second exon of the zDC gene were sorted. DEC-205+ and DCIR2+ cDCs from the zDC knockout mice were collected for comparison with wildtype cDCs. Three replicates per group. The wildtype samples have been previously analyzed and are available in the GEO database in Series GSE6259. The complete dataset representing: (1) the zDC knockout Samples and (2) the wildtype Samples from Series GSE6259 (re-processed using RMA), is linked below as a supplementary file.

2012-07-15 | E-GEOD-37995 | biostudies-arrayexpress

Plasmacytoid dendritic cell precursors give rise to conventional dendritic cells via a Siglec-H+ Zbtb46+ Ly6D+ intermediary stage

Project description:Plasmacytoid and conventional dendritic cells (pDC, and cDC) are generated from distinct lymphoid and myeloid progenitor cells in murine bone marrow. Despite the early separation of pDC and cDC lineages, CD11c+ MHCII-/lo Siglec-H+ CCR9lo pDC-like precursor cells are able to differentiate into both pDC and cDC. Single-cell transcriptomics and high-dimensional flow cytometry combined with cell fate analysis revealed the heterogeneity and commitment of subsets in this compartment. While Ly6D– cells within this fraction were cDC-committed and B220hi Ly6Dhi Zbtb46– cells were immediate precursors of pDCs, B220lo Ly6Dhi Zbtb46– cells still had the potential to generate cDCs in addition to pDCs. Transition to cDCs occurred via an intermediary stage marked by coexpression of Siglec-H, Ly6D and Zbtb46. Type I IFN stimulation limited cDC and promoted pDC output from these precursors, demonstrating their plasticity in response to inflammation. Thus, flexibility to divert to cDCs is retained in the pDC lineage at later differentiation stages.

2021-12-01 | GSE189780 | GEO

Tissue-specific differentiation of a circulating CCR9- pDC-like common dendritic cell precursor

Project description:Committed precursors of conventional dendritic cells (pre-cDCs) derived from the common DC progenitor which differentiate into cDC subpopulations in peripheral tissues have been identified, but committed precursors for plasmacytoid DCs (pDCs) have not been found. Here we show that CDP-derived ‘CCR9- MHCIIlow BST2+ Siglec-H+ pDCs from murine bone marrow which enter the circulation and peripheral tissues have a common DC precursor function in vivo in the steady state. Upon adoptive transfer the fate of CCR9- pDC-like precursors is governed by the tissues they enter. In the bone marrow and liver most transferred CCR9- pDC-like precursors differentiate into CCR9+ pDCs, whereas in peripheral lymphoid organs, lung and intestine they can give rise to CCR9+ pDCs and cDCs. Thus, CCR9- pDC-like cells are novel CDP-derived circulating DC precursors with pDC and cDC potential, whose final differentiation depends on tissue-specific factors allowing adaptation to local requirements. Total RNA obtained from CCR9- pDC-like common DC progenitors and CCR9+ pDCs was compared for differential gene expression. 3 independent isolations were performed for the 2 samples. 6 arrays were run in total.

2012-05-15 | E-GEOD-37996 | biostudies-arrayexpress

Tissue-specific differentiation of a circulating CCR9- pDC-like common dendritic cell precursor

2012-05-16 | GSE37996 | GEO

Transcription profiling of human plasmacytoid dentritic cells co-cultured with activated conventional dendritic cells

Project description:Two well-characterized blood dendritic cell populations, conventional (cDC) and plasmacytoid (pDC), exhibit multiple phenotypic, migratory and functional differences that suggest specialized and may be complementary and coordinated functions. To study this possible coordination, cDCs and pDCs from healthy blood donors were sorted and cDCs were stimulated either with LPS or R848 whereas pDCs were CFSE-labelled and maintained in IL3. Then, CFSE labelled-pDCs and stimulated-cDCs were mixed and co-cultured. Following this "conditioning", CFSE-pDCs were sorted again and further analyzed. Conditioned pDCs showed moderate phenotypic maturation and acquired allostimulatory capacity. Microarray and RT-PCR analyses showed the induction of different genes including chemokines and proinflammatory cytokines that were dependent on the stimulation received from the "conditioner" cDC. Additionally, the differential pattern of conditioning was confirmed by protein secretion analyses with the production of specific chemokines and cytokines by conditioned pDCs. Importantly, conditioning of pDCs by activated cDCs required cell-cell contact.

2011-01-20 | E-MEXP-2555 | biostudies-arrayexpress

Transcriptome comparison between Zbtb46-deficient and -sufficient group 3 innate lymphoid cells

Project description:We unexpectedly identify one unique subset of group 3 innate lymphoid cells (ILC3s) that co-expresses Zbtb46, a transcription factor that specifies conventional dendritic cells (cDCs). Zbtb46 is robustly expressed by CCR6+ lymphoid tissue inducer (LTi)-like ILC3s that are developmentally and phenotypically distinct from cDCs. To determine the function of Zbtb46 in ILC3s, we performed RNA sequencing on CCR6+ ILC3s sorted from the large intestine of Zbtb46 f/f and Rorc Cre Zbtb46 f/f mice at steady state.

2022-05-02 | GSE181865 | GEO

ChIP-Seq (H3K4me3, H3K27me3) of steady-state splenic classical dendritic cells from wild type, germ-free and IFNAR knockout mice

Project description:The epigenetic state of splenic cDCs from Wild Type (WT) mice, Germ Free (GF) and mice deficient for the Ifnar1 gene (IFNAR) was characterized by analyzing the occupancy of a major activating histone mark (H3K4me3) and a major repressive histone mark (H3K27me3). Splenic cDCs (CD3- CD19- CD45+ MHC-II+ CD11c+) were sorted to high purity by flow cytometry and subject to chromatin immunoprecipitation.

2018-06-30 | E-MTAB-5234 | biostudies-arrayexpress

ChIP-seq profiling of PU.1 binding sites in plasmacytoid and conventional mouse dendritic cells

Project description:Dendritic cells (DCs) are can be broadly divided into conventional (cDC) and plasmacytoid (pDC) subsets. Despite the importance of this lineage diversity, its genetic basis is not fully understood. ChIP-seq profiling of PU.1 binding sites in cDCs and pDCs revealed a key role for PU.1 in maintaining cDC identity.

2018-10-21 | GSE121544 | GEO

Microarray analysis of WT and Notch2-deficient classical DC subsets

Project description:Defense against attaching and effacing (A/E) bacteria requires the sequential generation of IL-23 and IL-22 to induce protective mucosal responses. While the critical source of IL-22 has been identified as CD4+ and Nkp46+ innate lymphoid cells (ILCs), the precise source of IL-23 is unclear. Here, we use genetic techniques to deplete specific classical dendritic cell (cDC) subsets and analyze immunity to the A/E pathogen Citrobacter rodentium. We find that Zbtb46+ cDCs, and specifically Notch2-dependent intestinal CD11b+ cDCs, but not Batf3-dependent CD103+ cDCs, are required for IL-23 production and immunity against C. rodentium. Notch2 controls cDC differentiation at a terminal step mediated by lymphotoxin signaling. Importantly, these results provide the first demonstration of a non-redundant function of CD11b+ cDCs in vivo. Analysis of Notch2-dependent genes in CD11b+ and DEC205+ splenic classical DC subsets. Splenocytes were harvested from littermate WT Notch2 f/f C57Bl/6 or Notch2 CD11c-cre C57Bl/6 mice and DC subsets sorted to >95% purity on the FACSAriaII.

2013-06-01 | E-GEOD-45681 | biostudies-arrayexpress

Microarray analysis of WT and Notch2-deficient classical DC subsets

2013-06-01 | GSE45681 | GEO

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