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Sca-1 expression defines different developmental stages of mouse PDC that show functional heterogeneity in the endosomal but not lysosomal TLR9 response

ABSTRACT: Plasmacytoid dendritic cells (PDC) play an important role in innate and adaptive immunity and were shown to be identical to previously described natural IFN-α-producing cells (NIP). Here, we describe two functionally distinct PDC subpopulations that are characterized by the differential expression of stem cell antigen-1 (Sca-1; Ly-6A/E). Sca-1- PDC are mainly found in the bone marrow, appear first during development, show a higher proliferative activity and represent the more precursor phenotype. Sca-1+ PDC are mostly located in secondary lymphoid organs and show higher expression of MHC class II molecules. Sca-1- PDC give rise to a Sca-1+ subset upon activation or in response to tissue-specific factors. Interestingly, in contrast to Sca-1- PDC, Sca-1+ PDC are defective in type I IFN production upon endosomal TLR9 stimulation, whereas lysosomal signaling via TLR9 is functional in both subsets. Gene expression analysis revealed that osteopontin (Opn) is strongly upregulated in Sca-1- PDC. This data provides evidence for the molecular basis of the observed functional heterogeneity, as the intracellular isoform of Opn couples TLR9 signaling to IFN-α expression. Taken together, our results indicate that Sca-1- PDC are an early developmental stage of PDC with distinct innate functions representing the true murine NIP.

ORGANISM(S): Mus musculus

PROVIDER: GSE42860 | GEO | 2013/12/21

SECONDARY ACCESSION(S): PRJNA183671

REPOSITORIES: GEO

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Sca-1 expression defines different developmental stages of mouse PDC that show functional heterogeneity in the endosomal but not lysosomal TLR9 response

Project description:Plasmacytoid dendritic cells (PDC) play an important role in innate and adaptive immunity and were shown to be identical to previously described natural IFN-M-NM-1-producing cells (NIP). Here, we describe two functionally distinct PDC subpopulations that are characterized by the differential expression of stem cell antigen-1 (Sca-1; Ly-6A/E). Sca-1- PDC are mainly found in the bone marrow, appear first during development, show a higher proliferative activity and represent the more precursor phenotype. Sca-1+ PDC are mostly located in secondary lymphoid organs and show higher expression of MHC class II molecules. Sca-1- PDC give rise to a Sca-1+ subset upon activation or in response to tissue-specific factors. Interestingly, in contrast to Sca-1- PDC, Sca-1+ PDC are defective in type I IFN production upon endosomal TLR9 stimulation, whereas lysosomal signaling via TLR9 is functional in both subsets. Gene expression analysis revealed that osteopontin (Opn) is strongly upregulated in Sca-1- PDC. This data provides evidence for the molecular basis of the observed functional heterogeneity, as the intracellular isoform of Opn couples TLR9 signaling to IFN-M-NM-1 expression. Taken together, our results indicate that Sca-1- PDC are an early developmental stage of PDC with distinct innate functions representing the true murine NIP. The dataset comprises eight samples divided into two sample groups consisting of Sca-1(-) and Sca-1(+) PDCs collected from in vitro culture of differentiated bone marrow precursor cells using mFlt3-L

2013-12-21 | E-GEOD-42860 | biostudies-arrayexpress

Bruton's Tyrosine Kinase Regulates TLR9 but not TLR7 Signaling in Human pDCs

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2015-10-24 | E-GEOD-41825 | biostudies-arrayexpress

Bruton's Tyrosine Kinase Regulates TLR9 but not TLR7 Signaling in Human pDCs

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IRF-5 and IRF-8 govern the response of Human Plasmacytoid Dendritic Cells following TLR9 ligation

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TLR-mediated type I IFN induction in pDCs requires the rapamycin-sensitive PI3K-mTOR-p70S6K pathway

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IRF-5 and IRF-8 govern the response of Human Plasmacytoid Dendritic Cells following TLR9 ligation

Project description:Synthetic oligonucleotides (ODNs) containing CpG motifs stimulate human plasmacytoid dendritic cells (pDCs) to produce type-1 interferons (IFN) and pro-inflammatory cytokines. Previous studies demonstrated that interferon regulatory factors (IRFs) played a central role in mediating CpG-induced pDC activation. This work explores the inverse effects of IRF-5 and IRF-8 on CpG dependent gene expression. Results from RNA interference and microarray studies indicate that IRF-5 up-regulates TLR9-driven gene expression whereas IRF-8 down-regulates the same genes. Several findings support the conclusion that IRF-8 inhibits TLR9 dependent gene expression by directly blocking the activity of IRF-5. First, the inhibitory activity of IRF-8 is only observed when IRF-5 is present. Second, proximity ligation analysis shows that IRF-8 and IRF-5 co-localize within the cytoplasm of resting human pDC and co-translocate to the nucleus after CpG stimulation. Taken together, these findings suggest that two transcription factors with opposing functions control TLR9 signaling in human pDCs. CAL-1 cells were transfected with siRNA targeting IRF-5 (IRF-5si) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats). CAL-1 cells were transfected with siRNA targeting IRF-8 (IRF-8si) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats). CAL-1 cells were transfected with control siRNA (Contsi) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats).

2016-06-01 | E-GEOD-70429 | biostudies-arrayexpress

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Transcriptional repression of IRF7 by MYC is critical for antiviral immune response in human pDC [ChIP-seq]

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Transcriptional repression of IRF7 by MYC is critical for antiviral immune response in human pDC [pDC]

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