ScRNA-Seq to study the impact of HIV-1 on DC biology [PreDC_Single_Cell_Exp2]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE201328 | GEO | 2023/01/13
REPOSITORIES: GEO
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Project description:Pre-DC have been initially described through their ontogeny. Our lab reported for the first time a pre-DC functional specificity in the context of HV-1 capture, infection and in vitro transmission as a consequence of their constitutive expression of Siglec-1. However, pre-DC immune response to viral exposure remained to be studied. This study aim to decipher innate immune response of pre-DC when exposed to HIV-1.
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Project description:Axl+DC have been initially described through their ontogeny. Our lab reported for the first time an Axl+ DC functional specificity in the context of HV-1 capture, infection and in vitro transmission as a consequence of their constitutive expression of Siglec-1. However, Axl+DC immune responses to viral exposure remained to be studied. This study aim to decipher innate immune response of Axl+DC when exposed to HIV-1 in comparison to other DC subtypes.
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Project description:Human immune cell subsets develop in immunodeficient mice following reconstitution with human CD34+ haematopoietic stem cells. These “humanized” mice are useful models to study human immunology and human-tropic infections, autoimmunity and cancer. However, some human immune cell subsets are unable to fully develop or acquire full functional capacity due to a lack of cross-reactivity of many growth factors and cytokines between species. “Classical” (c) DC arise from a separate precursor to monocytes and initiate and direct T cell responses. In mice they can be further categorized into cDC1, which mediate Th1 and CD8+ T cell responses, and cDC2, which mediate Th2 and Th17 responses. The gene expression profiles and phenotype human CD141+ DC and CD1c+ DC subsets align with mouse cDC1 and cDC2 respectively but there are also key interspecies differences. Human CD141+ DC and CD1c+ DC develop in humanized mice but the extent to which they resemble their human blood counterparts is not yet known. We therefore analyzed the gene expression profiles of CD141+ DC and CD1c+ DC in humanized mice and demonstrated that they closely resemble those in human blood, making this an attractive model in which to study human DC in vitro or on vivo. We further used this model to explore changes in DC subsets after activation with TLR3 and TLR7/8 ligands, poly I:C and R848 in vivo. A core panel of genes consistent with DC maturation status were upregulated by both subsets. R848 specifically upregulated genes associated with Th17 responses by CD1c+ DC, whilst poly I:C upregulated IFN-λ genes specifically by CD141+ DC. Thus CD141+ DC and CD1c+ DC share a similar activation profiles in vivo but also have induce unique signatures that support specialized roles in CD8+ T cell priming and Th17 responses respectively. '
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Project description:Dendritic cells (DC) are professional antigen-presenting cells that orchestrate immune responses. Important questions on the origins and differentiation paths of human DC populations remain elusive. Here we combined two high-dimensional technologies, single-cell mRNA sequencing and mass cytometry to define and characterize CD33+CD45RA+ DC precursors (pre-DC) present in human blood. In this study, we showed that a previously understimated pre-DC population shares surface markers with plasmacytoid DC (pDC), but has distinct functional properties that were previously attributed to pDC. Finally, we trace the origin of DCs from BM to peripheral blood and reveal that pre-DC comprise three sub-populations - 1 uncommitted sub-population and 2 lineage-committed sub-populations. The discovery of committed pre-DC populations in present in human peripheral blood confirms the existence of DC as a distinct hematopoietic lineage and opens promising new avenues for the therapeutic exploitation of DC subset-specific targeting.
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Project description:Dendritic cells (DC) are professional antigen-presenting cells that orchestrate immune responses. The human DC population comprises two main functionally-specialized lineages, whose origins and differentiation pathways remain incompletely defined. Here we combine two high-dimensional technologies — single-cell mRNA sequencing and Cytometry by Time-of-Flight (CyTOF), to identify human blood CD123+CD33+CD45RA+ DC precursors (pre-DC). Pre-DC share surface markers with plasmacytoid DC (pDC) but have distinct functional properties that were previously attributed to pDC. Tracing the differentiation of DC from the bone marrow to the peripheral blood revealed that the pre-DC compartment contains distinct lineage-committed sub-populations including one early uncommitted CD123high pre-DC subset and two CD45RA+CD123low lineage-committed subsets exhibiting functional differences. The discovery of multiple committed pre-DC populations opens promising new avenues for the therapeutic exploitation of DC subset-specific targeting.
2017-05-01 | GSE98052 | GEO
Project description:Dendritic cells (DC) are professional antigen-presenting cells that orchestrate immune responses. The human DC population comprises two main functionally-specialized lineages, whose origins and differentiation pathways remain incompletely defined. Here we combine two high-dimensional technologies — single-cell mRNA sequencing and Cytometry by Time-of-Flight (CyTOF), to identify human blood CD123+CD33+CD45RA+ DC precursors (pre-DC). Pre-DC share surface markers with plasmacytoid DC (pDC) but have distinct functional properties that were previously attributed to pDC. Tracing the differentiation of DC from the bone marrow to the peripheral blood revealed that the pre-DC compartment contains distinct lineage-committed sub-populations including one early uncommitted CD123high pre-DC subset and two CD45RA+CD123low lineage-committed subsets exhibiting functional differences. The discovery of multiple committed pre-DC populations opens promising new avenues for the therapeutic exploitation of DC subset-specific targeting.
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Project description:Human mononuclear phagocytes comprise phenotypically and functionally overlapping subsets of dendritic cells (DC) and monocytes, but their identification remains elusive. By integrating high-dimensional single-cell protein and RNA expression data, we clearly delineated monocytes from conventional DC2 (cDC2), identifying new markers including CD88/CD89 for monocytes and HLA-DQ/FcRI for cDC2, allowing their unambiguous characterization in blood and tissues. We also show that cDC2 can be subdivided into phenotypically and functionally distinct subsets based on CD5, CD163 and CD14 expression, including a unique subset of circulating inflammatory CD5-CD163+CD14+ cells related to previously defined DC3. These inflammatory DC3 were expanded in systemic lupus erythematosus patients, correlating with disease activity. Unravelling the heterogeneity of DC sub-populations in health and disease paves the way for specific DC subset-targeting therapies.
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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.
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