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Mapping the human DC lineage through the integration of high dimensional techniques

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE98052 | GEO | 2017/05/01

SECONDARY ACCESSION(S): PRJNA383814

REPOSITORIES: GEO

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Mapping the human DC lineage through the integration of high dimensional techniques

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 | GSE98011 | GEO

Transcriptome profiles of human pre-DC and DC subsets in peripheral blood

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.

2017-05-21 | GSE80171 | 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

Functional and transcriptional heterogeneity of human hemopoietic lympho-myeloid progenitors

Project description:Cord blood (CB) samples from normal donors were obtained with informed consent. Fresh CB samples were processed within 18-34h after collection. Mononuclear cells were isolated and CD34+ fraction was separated. CB CD34+ enriched fraction was lineage depleted by staining with purified anti-human CD2, CD3, CD4, CD7, CD8a, CD11b, CD14, CD19, CD20, CD56, CD235a followed by Qdot 605 conjugated goat F(ab')2 anti-mouse IgG (H+L). Cells were also stained with anti-human CD38-FITC, CD45RA-PE or -BV650, CD123-PE Cy7, CD90-biotin, CD34- PerCP and CD10-APC. Finally, cells were incubated with streptavidin-conjugated APC-eF780 and Hoechst 33258 (Invitrogen, final concentration: 1 g/ml). Populations were defined, as follows: HSC - Lin-CD34+CD38-CD90+CD45RA-CD10-, MPP - Lin-CD34+CD38-CD90-CD45RA-CD10-, LMPP - Lin-CD34+CD38-CD90-/loCD45RA+CD10-, MLP - Lin-CD34+CD38-CD90-/loCD45RA+CD10+, GMP - Lin-CD34+CD38+CD123+CD45RA+CD10-, CMP - Lin-CD34+CD38+CD123+CD45RA-CD10-, MEP - Lin-CD34+CD38+CD123-CD45RA-CD10-.

2017-10-03 | E-MTAB-5456 | biostudies-arrayexpress

Tissue-specific factors differentially regulate the expression of antigen-processing enzymes during dendritic cell ontogeny

Project description:Dendritic cells (DC) form a collection of antigen-presenting cells that are distributed throughout the body. Conventional DC (cDC) which include the cDC1 and cDC2 subsets, and plasmacytoid DC (pDC) constitute the two major ontogenically distinct DC populations. The pDC complete their differentiation in bone-marrow (BM) while the cDC subsets derive from pre-committed bone-marrow (BM) precursors, the pre-cDC, that seed lymphoid and non-lymphoid tissues where they further differentiate into mature cDC1 and cDC2. Within different tissues, cDC express distinct phenotype and function. Notably cDC in the thymus are exquisitely efficient at processing and presenting antigens in the class II pathway, while in the spleen they do so only upon maturation induced by danger signals. To appraise this functional heterogeneity, we examined the regulation of the expression of distinct antigen-processing enzymes during DC ontogeny. We analyzed the expression of cathepsin S (CTSS), cathepsin L (CTSL) and thymus specific serine protease (TSSP), three major antigen-processing enzymes regulating class II presentation in cDC, by DC BM precursors and immature and mature cDC from spleen and thymus. We found that pre-cDC in the BM express relatively high levels of these different proteases. Then, their expression is modulated in a tissue-specific and subset–specific manner with immature and mature thymic cDC expressing overall higher levels than immature splenic cDC. On the other hand, TSSP expression level is selectively down-regulated in spleen pDC while CTSS and CTSL are both increased in thymic and splenic pDC. Hence tissue-specific factors program the expression levels of these different proteases during DC differentiation thus conferring tissue-specific function to the different DC subsets.

2020-01-29 | GSE144421 | GEO

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

2012-05-16 | GSE37996 | GEO

A lncRNA identifies Irf8 enhancer element in negative feedback control of dendritic cell differentiation

Project description:Dendritic cells (DC) are professional antigen presenting cells that develop from multipotent progenitors (MPP) and DC committed common DC progenitors (CDP) and further differentiate into different subsets: classical DC type 1 and 2 (cDC1 and cDC2, respectively) and plasmacytoid DC (pDC). In this study MPP, CDP, cDC1, cDC2 and pDC were obtained in a two-step in vitro culture system according to Felker et al., J. Immunol. 185, 5326-5335, 2010. Briefly, mouse bone marrow cells were first amplified with a specific cytokine cocktail and then induced to differentiate into DC with Flt3 ligand. MPP, CDP, cDC1, cDC2 and pDC were obtained by FACS sorting as follows: MPP: Gr1- CD117hi CD135low/-; CDP: Gr1- CD117int CD135+ CD115+; cDC1: CD11c+ CD11blow/- XCR1+; cDC2: CD11c+ CD11b+ XCR1- and pDC: CD11c+ CD11b- B220+. FACS sorted cells were then subjected to Omni-ATAC-seq, nuclear-titrated (NuTi) Capture-C targeting Irf8 promoter, and RNA-seq analysis. ATAC-seq data of cDC1 and pDC are published (Li et al., Genome Biol. 20, 45, 2019; GSE118221). ATAC-seq data of MPP, CDP and cDC2, NuTi Capture-C and RNA-seq data of MPP, CDP, cDC1, cDC2 and pDC are published here. CD11c+ CD11b+ B220- cDC and CD11c+ CD11b- B220+ pDC were obtained by FACS sorting and subjected to ChIP-seq analysis of IRF8 and are published here.

2023-03-01 | GSE198651 | GEO

TRANSITIONAL DENDRITIC CELLS ARE DISTINCT FROM CONVENTIONAL DC2 PRECURSORS AND MEDIATE PRO-INFLAMMATORY ANTIVIRAL RESPONSES

Project description:High-dimensional approaches revealed emerging heterogeneity within dendritic cells (DC), including a population of transitional DC (tDC) present in mouse and human. However, tDC origin and relationship to other DC subsets are not fully understood. Here, we show that tDC are distinct from other well-characterized DC and conventional DC precursors (pre-cDC). We demonstrate that tDC originate from bone marrow progenitors shared with plasmacytoid DC (pDC). In the periphery, tDC contribute to the pool of ESAM+ type 2 DC (DC2), and these DC2 harbor pDC-related developmental features. Different from pre-cDC, tDC have lower turnover, capture antigen, respond to stimuli, and activate antigen-specific naïve T cells, all characteristics of differentiated DC. Different from pDC, viral sensing by tDC results in IL-1b secretion and fatal immune pathology in a murine coronavirus model. Our findings suggest that tDC are a distinct pDC-related subset with a DC2 differentiation potential and unique pro-inflammatory function during viral infections.

2023-05-21 | GSE198553 | GEO

NanoSTRING dendritic cell subpopulation

Project description:High-dimensional approaches have revealed emerging heterogeneity within dendritic cells (DC), including a population of transitional DC (tDC) present in mouse and human. However, tDC origin and relationship to other DC subsets are not fully understood because their phenotype partially overlaps with previous definitions of conventional DC precursors (pre-cDC). Here, we show that tDC are distinct from other well-characterized DC and pre-cDC. By combining single-cell transcriptomics, high-dimensional immunophenotyping, lineage tracing and adoptive transfer experiments, we demonstrate that murine tDC originate from bone marrow progenitors shared with plasmacytoid DC (pDC) that are distinct from CD115-expressing conventional DC progenitors. In the periphery, tDC contribute to the pool of Esam+ type 2 DC (DC2), and these tDC-derived DC2 harbor pDC-related developmental features. tDC have lower turnover than pre-cDC2, capture antigen, respond to stimuli, and potently antigen-specific naïve T cells, all characteristics of differentiated DC. Different from pDC, viral sensing by tDC results in IL-1β secretion and fatal immune pathology in a model of murine coronavirus. Our findings suggest that tDC are a distinct pDC-related lineage with a DC2 differentiation potential and unique pro-inflammatory function during viral infections. The objective of this experiment was to evaulate the transcriptional changes in various dendritic cell subpopulations

2023-05-23 | GSE233143 | GEO

Epigenetic Program and Transcription Factor Circuitry of Dendritic Cell Development

Project description:Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC. Specific histone marks in CDP reveal a DC-primed epigenetic signature, which is maintained and reinforced during DC differentiation. Epigenetic marks and transcription factor PU.1 occupancy increasingly coincide upon DC differentiation. By integrating PU.1 occupancy and gene expression we devised a transcription factor regulatory circuitry for DC commitment and subset specification. The circuitry provides the transcription factor hierarchy that drives the sequel MPP-CDP-cDC/pDC, including Irf4, Irf8, Tcf4, Spib and Stat factors. The circuitry also includes feedback loops inferred for individual or multiple factors, which stabilize distinct stages of DC development and DC subsets. In summary, here we describe the basic regulatory circuitry of transcription factors that drives DC development.

2015-12-09 | GSE64767 | GEO

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