Unique CD8+ T Cell Priming by Antigen Presenting Plasmacytoid Dendritic Cells Compared to Conventional Dendritic Cells
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PROVIDER: PRJNA1086965 | ENA |
REPOSITORIES: ENA
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Project description:Cholangitis mouse models were characterised by selective intrahepatic expansion of type 2 conventional dendritic cells, whereas plasmacytoid and type 1 conventional dendritic cells were not expanded. Expansion of type 2 conventional dendritic cells in human PSC lesions was confirmed by histology. Depletion studies revealed a pro-inflammatory role of type 2 conventional dendritic cells. Single-cell transcriptomics confirmed inflammatory maturation of the intrahepatic type 2 conventional dendritic cells and identified dendritic cell-derived inflammatory mediators.
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Project description:Clonal lineage tracing reveals shared origin of conventional and plasmacytoid dendritic cells
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Project description:The interferon-producing plasmacytoid dendritic cells (PDC) share common progenitors with antigen-presenting classical dendritic cells (cDC), yet they possess distinct morphology and molecular features resembling those of lymphocytes. It is unclear whether the unique cell fate of PDC is actively maintained in the steady state. We report that the deletion of transcription factor E2-2 from mature peripheral PDC caused their spontaneous differentiation into cells with cDC properties. This included the loss of PDC markers, increase in MHC class II expression and T cell priming capacity, acquisition of dendritic morphology and induction of cDC signature genes. Genome-wide chromatin immunoprecipitation revealed direct binding of E2-2 to key PDC-specific and lymphoid genes, as well as to certain genes enriched in cDC. Thus, E2-2 actively maintains the cell fate of mature PDC and opposes the “default” cDC fate, in part through direct regulation of lineage-specific gene expression programs.
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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.
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Project description:The interferon-producing plasmacytoid dendritic cells (PDC) share common progenitors with antigen-presenting classical dendritic cells (cDC), yet they possess distinct morphology and molecular features resembling those of lymphocytes. It is unclear whether the unique cell fate of PDC is actively maintained in the steady state. We report that the deletion of transcription factor E2-2 from mature peripheral PDC caused their spontaneous differentiation into cells with cDC properties. This included the loss of PDC markers, increase in MHC class II expression and T cell priming capacity, acquisition of dendritic morphology and induction of cDC signature genes. Genome-wide chromatin immunoprecipitation revealed direct binding of E2-2 to key PDC-specific and lymphoid genes, as well as to certain genes enriched in cDC. Thus, E2-2 actively maintains the cell fate of mature PDC and opposes the “default” cDC fate, in part through direct regulation of lineage-specific gene expression programs. Cells of the human PDC lymphoma line CAL-1 (Maeda et al., Int J Hematol 2005) were crosslinked with formaldehyde, sonicated, and subjected to immunoprecipitation with anti-E2-2 mAb (Bain et al., Mol Cell Biol 1993) or mouse IgG control as described (Cisse et al., Cell 2008). After crosslink reversal, the isolated chromatin was amplified, labeled and hybridized to Human Promoter ChIP-on-chip Microarray Set (Agilent Technologies). Hybridized microarrays were scanned and analyzed using DNA Analytics software (Agilent Technologies).
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Project description:Developmental origins of dendritic cells (DCs) including conventional DCs (cDCs, comprising cDC1 and cDC2 subsets) and plasmacytoid DCs (pDCs) remain unclear. We studied DC development in unmanipulated adult mice using inducible lineage tracing combined with clonal DNA "barcoding" and single-cell transcriptome and phenotype analysis (CITE-Seq). Inducible tracing of Cx3cr1+ hematopoietic progenitors in the bone marrow showed that they simultaneously produce all DC subsets including pDCs, cDC1s and cDC2s. Clonal tracing of hematopoietic stem cells (HSCs) and of Cx3cr1+ progenitors revealed clone sharing between cDC1s and pDCs, but not between the two cDC subsets or between pDCs and B cells. Accordingly, CITE-Seq analyses of differentiating HSCs and Cx3cr1+ progenitors identified progressive stages of pDC development including Cx3cr1+ Ly-6D+ propDCs that were distinct from lymphoid progenitors. These results reveal the shared origin of pDCs and cDCs, and suggest a revised scheme of DC development whereby pDCs share clonal relationship with cDC1s
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