Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA182314 | ENA |
REPOSITORIES: ENA
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Project description:Background: Dendritic cells (DCs) are critical for regulating CD4 and CD8 T cell immunity, controlling Th1, Th2, and Th17 bias, generating inducible Tregs, and inducing tolerance. Multiple DC subsets have been identified in the mouse that are thought to have evolved to control these different immune outcomes. However, how these subsets differentially respond to inflammatory and/or tolerogenic signals in order to accomplish their divergent functionality remains unclear. Results: We analysed the responses of murine, splenic CD8 and CD11b DC subsets to in-vivo stimulation with lipopolysaccharide using RNA-Seq and systems biology approaches and observed responses are highly subset-specific. We reanalysed multiple datasets from the literature and show that these subset responses are obscured when analysing signaling at the population level. We show that the subset-specificity is due to the unique regulation of distinct TLR4 pathway modulators that ‘fine-tune’ a common TLR4 cascade rather and not due to major differences in signaling pathways or transcription factors. Conclusions: We propose the Pathway Modulation Model wherein common signaling pathways are regulated by unique sets of modulators allowing for distinct immune responses in closely related DC subsets. We extend these observations using analagous datasets from the literature and show that our model provides a global mechanism for generating cell subset-specific signaling in multiple subpopulations in mouse and man. Splenic CD8 and CD11b DC subsets from LPS stimulated (10 pooled animals) and Control (5 pooled animals) mice were analysed by RNA-Seq.
2014-07-01 | E-GEOD-42573 | biostudies-arrayexpress
Project description:The dendritic cell (DC)-derived chemokine CCL17, a ligand of CCR4, has been shown to promote various inflammatory diseases such as atopic dermatitis, atherosclerosis, and inflammatory bowel disease. Under steady state conditions, and even after systemic stimulation with lipopolysaccharide, CCL17 is not expressed in resident splenic DC as opposed to CD8-CD11b+ lymph node (LN) DC, which produce large amounts of CCL17, in particular after maturation. Upon systemic NKT cell activation through alpha-galactosylceramide stimulation, however, CCL17 can be upregulated in both CD8- and CD8+ splenic DC subsets and enhances cross-presentation of exogenous antigens. Based on genome wide expression profiling, we now show that splenic DC are susceptible to Interferon-gamma (IFNgamma) mediated suppression of CCL17, whereas LN DC are much less responsive to IFNgamma and downregulate the IFNgamma receptor. Under inflammatory conditions, particularly in the absence of IFNgamma signaling in IFNgamma receptor deficient mice, CCL17 expression is strongly induced in a major proportion of splenic DC by the action of granulocyte-macrophage colony stimulating factor (GM-CSF) in concert with interleukin (IL)-4. Our findings demonstrate that the local cytokine milieu and differential cytokine responsiveness of DC subsets regulate lymphoid organ specific immune responses at the level of chemokine expression. 15 h after pretreatment with 100 µg LPS, spleens and LN (MLN and PLN) from CCL17E/+ mice were harvested and DC-enriched cell suspensions of the respective organs were stained for NK1.1, CD8alpha, CD11c and CD11b. For isolation of LN DC, NK1.1-CD8alpha-CD11c+CD11b+ cells expressing CCL17/EGFP were sorted (FACSAria). Splenic DC were sorted in parallel from the same mice, but only CCL17/EGFP-negative cells expressing the same markers were selected. After the sort, cells were immediately lysed in Trizol (Invitrogen) before storage at -80°C for RNA isolation.
2013-09-19 | E-GEOD-43456 | biostudies-arrayexpress
Project description:Dendritic cells (DCs) are critical in mediating immunity to pathogens, vaccines, tumors and tolerance to self. Significant progress has been made in the study of DC subsets in murine models but the translation of these findings to human DC immunobiology has not been fully realized. Murine splenic CD8+ DC and CD103+ DC possess potent antigen cross-presenting capacity. Although recent evidence points to human blood CD141+ DCs as the functional equivalent of CD8+ DC, the precise identity of the human migratory cross-presenting DC has remained elusive. We performed phenotypic and functional analyses to interrogate the DC compartment of human non-lymphoid tissues and identified three distinct subsets: i) CD141high DCs, ii) CD1c DCs and iii) CD14+ DCs. Only CD141high DCs were capable of cross-presenting soluble antigen. Comparative transcriptome analysis of steady state monocyte and DC subsets between mouse and human confirmed conservation between species, aligning the following subsets together: i) human CD141high DCs with mouse CD8+ and CD103+ DCs, ii) human CD1c+ DCs with mouse CD4+ DCs and iii) human CD14+ DC with mouse monocyte subsets. The lack of positive association between human CD1c+ DCs and mouse non-lymphoid tissue CD11b+ DCs highlights heterogeneity and predicts the existence of a monocyte-like cell within the CD11b+ DCs. Gene expression analysis using total RNA from specific human and mouse monocyte and dendritic cell subsets purified by FACS.
2012-07-11 | E-GEOD-35457 | biostudies-arrayexpress
Project description:Dendritic cells (DCs) are critical in mediating immunity to pathogens, vaccines, tumors and tolerance to self. Significant progress has been made in the study of DC subsets in murine models but the translation of these findings to human DC immunobiology has not been fully realized. Murine splenic CD8+ DC and CD103+ DC possess potent antigen cross-presenting capacity. Although recent evidence points to human blood CD141+ DCs as the functional equivalent of CD8+ DC, the precise identity of the human migratory cross-presenting DC has remained elusive. We performed phenotypic and functional analyses to interrogate the DC compartment of human non-lymphoid tissues and identified three distinct subsets: i) CD141high DCs, ii) CD1c DCs and iii) CD14+ DCs. Only CD141high DCs were capable of cross-presenting soluble antigen. Comparative transcriptome analysis of steady state monocyte and DC subsets between mouse and human confirmed conservation between species, aligning the following subsets together: i) human CD141high DCs with mouse CD8+ and CD103+ DCs, ii) human CD1c+ DCs with mouse CD4+ DCs and iii) human CD14+ DC with mouse monocyte subsets. The lack of positive association between human CD1c+ DCs and mouse non-lymphoid tissue CD11b+ DCs highlights heterogeneity and predicts the existence of a monocyte-like cell within the CD11b+ DCs. Gene expression analysis using total RNA from specific human and mouse monocyte and dendritic cell subsets purified by FACS.
2012-07-11 | E-GEOD-35458 | biostudies-arrayexpress
Project description:Dendritic cells (DCs) are critical in mediating immunity to pathogens, vaccines, tumors and tolerance to self. Significant progress has been made in the study of DC subsets in murine models but the translation of these findings to human DC immunobiology has not been fully realized. Murine splenic CD8+ DC and CD103+ DC possess potent antigen cross-presenting capacity. Although recent evidence points to human blood CD141+ DCs as the functional equivalent of CD8+ DC, the precise identity of the human migratory cross-presenting DC has remained elusive. We performed phenotypic and functional analyses to interrogate the DC compartment of human non-lymphoid tissues and identified three distinct subsets: i) CD141high DCs, ii) CD1c DCs and iii) CD14+ DCs. Only CD141high DCs were capable of cross-presenting soluble antigen. Comparative transcriptome analysis of steady state monocyte and DC subsets between mouse and human confirmed conservation between species, aligning the following subsets together: i) human CD141high DCs with mouse CD8+ and CD103+ DCs, ii) human CD1c+ DCs with mouse CD4+ DCs and iii) human CD14+ DC with mouse monocyte subsets. The lack of positive association between human CD1c+ DCs and mouse non-lymphoid tissue CD11b+ DCs highlights heterogeneity and predicts the existence of a monocyte-like cell within the CD11b+ DCs.
2012-07-12 | GSE35458 | GEO
Project description:Dendritic cells (DCs) are critical in mediating immunity to pathogens, vaccines, tumors and tolerance to self. Significant progress has been made in the study of DC subsets in murine models but the translation of these findings to human DC immunobiology has not been fully realized. Murine splenic CD8+ DC and CD103+ DC possess potent antigen cross-presenting capacity. Although recent evidence points to human blood CD141+ DCs as the functional equivalent of CD8+ DC, the precise identity of the human migratory cross-presenting DC has remained elusive. We performed phenotypic and functional analyses to interrogate the DC compartment of human non-lymphoid tissues and identified three distinct subsets: i) CD141high DCs, ii) CD1c DCs and iii) CD14+ DCs. Only CD141high DCs were capable of cross-presenting soluble antigen. Comparative transcriptome analysis of steady state monocyte and DC subsets between mouse and human confirmed conservation between species, aligning the following subsets together: i) human CD141high DCs with mouse CD8+ and CD103+ DCs, ii) human CD1c+ DCs with mouse CD4+ DCs and iii) human CD14+ DC with mouse monocyte subsets. The lack of positive association between human CD1c+ DCs and mouse non-lymphoid tissue CD11b+ DCs highlights heterogeneity and predicts the existence of a monocyte-like cell within the CD11b+ DCs.
2012-07-12 | GSE35457 | GEO
Project description:The dendritic cell (DC)-derived chemokine CCL17, a ligand of CCR4, has been shown to promote various inflammatory diseases such as atopic dermatitis, atherosclerosis, and inflammatory bowel disease. Under steady state conditions, and even after systemic stimulation with lipopolysaccharide, CCL17 is not expressed in resident splenic DC as opposed to CD8-CD11b+ lymph node (LN) DC, which produce large amounts of CCL17, in particular after maturation. Upon systemic NKT cell activation through alpha-galactosylceramide stimulation, however, CCL17 can be upregulated in both CD8- and CD8+ splenic DC subsets and enhances cross-presentation of exogenous antigens. Based on genome wide expression profiling, we now show that splenic DC are susceptible to Interferon-gamma (IFNgamma) mediated suppression of CCL17, whereas LN DC are much less responsive to IFNgamma and downregulate the IFNgamma receptor. Under inflammatory conditions, particularly in the absence of IFNgamma signaling in IFNgamma receptor deficient mice, CCL17 expression is strongly induced in a major proportion of splenic DC by the action of granulocyte-macrophage colony stimulating factor (GM-CSF) in concert with interleukin (IL)-4. Our findings demonstrate that the local cytokine milieu and differential cytokine responsiveness of DC subsets regulate lymphoid organ specific immune responses at the level of chemokine expression.
2013-09-19 | GSE43456 | GEO
Project description:Background: Dendritic cells (DCs) are critical for regulating CD4 and CD8 T cell immunity, controlling Th1, Th2, and Th17 bias, generating inducible Tregs, and inducing tolerance. Multiple DC subsets have been identified in the mouse that are thought to have evolved to control these different immune outcomes. However, how these subsets differentially respond to inflammatory and/or tolerogenic signals in order to accomplish their divergent functionality remains unclear. Results: We analysed the responses of murine, splenic CD8 and CD11b DC subsets to in-vivo stimulation with lipopolysaccharide using RNA-Seq and systems biology approaches and observed responses are highly subset-specific. We reanalysed multiple datasets from the literature and show that these subset responses are obscured when analysing signaling at the population level. We show that the subset-specificity is due to the unique regulation of distinct TLR4 pathway modulators that ‘fine-tune’ a common TLR4 cascade rather and not due to major differences in signaling pathways or transcription factors. Conclusions: We propose the Pathway Modulation Model wherein common signaling pathways are regulated by unique sets of modulators allowing for distinct immune responses in closely related DC subsets. We extend these observations using analagous datasets from the literature and show that our model provides a global mechanism for generating cell subset-specific signaling in multiple subpopulations in mouse and man.
2014-07-01 | GSE42573 | GEO
Project description:Dendritic cells (DCs) in tissues and lymphoid organs comprise distinct functional subsets that differentiate in situ from circulating progenitors. Tissue-specific signals that regulate DC subset differentiation are poorly understood. We report that DC-specific deletion of the Notch2 receptor caused a reduction of DC populations in the spleen. Within the splenic CD11b+ DCs, Notch signaling blockade ablated a distinct population marked by high expression of adhesion molecule Esam. The Notch-dependent Esamhi DC subset also required lymphotoxin beta receptor signaling, proliferated in situ and facilitated efficient CD4+ T cell priming. The Notch-independent Esamlo DCs expressed monocyte-related genes and showed superior cytokine responses. In addition, Notch2 deletion led to the loss of CD11b+ CD103+ DCs in the intestinal lamina propria and to the corresponding decrease of IL-17-producing CD4+ T cells in the intestine. Thus,Notch2 is a common differentiation signal for T cell-priming CD11b+ DC subsets in the spleen and intestine. We compared genome-wide expression profiles of wild-type Esam(hi) and Esam(lo) splenic CD11b+ DC populations, along with CD11b+ DCs from DC-RBPJΔ mice. Spleens from 2-3 Cx3cr1-GFP+ RBPJflox/flox CD11c-Cre+ mice or Cx3cr1-GFP+ RBPJflox/flox Cre-negative littermate controls were isolated, pooled and depleted of lymphoid and erythroid cells by negative selection on MACS columns. Live cells were stained for surface expression of CD11c, CD11b and Esam. CD11c(hi) CD11b+ DCs from control mice could be separated into Esam(lo) GFP(hi) versus Esam(hi) GFP(lo) subsets. CD11c(hi) CD11b+ DCs from RBPJ-targeted mice spleens were uniformly Esam(lo) GFP(hi). The two subsets from control mice and single Esam(lo) GFP(hi) subset from RBPJ-targeted mice were sorted using FACSAria II flow sorter and analyzed using GeneChip Mouse Gene 1.0 ST Array (Affymetrix).
2011-10-31 | E-GEOD-31551 | biostudies-arrayexpress
Project description:The close functional relationship between macrophages and dendritic cells has long been recognised. Here, we have examined the gene expression profiles of splenic macrophages and the splenic resident dendritic cell subsets, and demostrate that macrophages and DC show different gene expression profiles. Further, we show that the DC subsets are closer to one another in gene expression profile than they are to macrophages. We here identify a list of differentially expressed genes between the DC subsets, and between DC and macrophages Splenic macrophages, CD8+ and CD8- cDC were analyzed
2011-06-17 | E-GEOD-30022 | biostudies-arrayexpress