Effect of HIV infection on co-stimulatory capacity of dendritic cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE21017 | GEO | 2011/03/15
SECONDARY ACCESSION(S): PRJNA125763
REPOSITORIES: GEO
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Project description:HIV uses dendritic cells as a carrier to infect its target CD4+ T cells. At the same time, it also hampers DCs function in terms of their T cell stimulatory capacity and cytokine secretion. We have shown that HIV causes reduction in the expression of co-stimulatory molecules, CD80 and CD86 by DCs at the mRNA level irrespective of the viral subtype or the mode in DC-HIV interaction. The microarray experiments were performed to understand the changes in the transcription factor profile of HIV infected DCs which may in turn lead to reduced CD80/CD86 expression as well as the effect of HIV infection on other co-stimulatory molecules on DCs. The data suggests that TFs NFKB1, NFKB2, REL and MYB may be responsible for the observed decrease in CD80 and CD86 expression and that HIV infection also hampers the expression of other co-stimulatory molecules like CD70, CD30, 4-1BB, OX40L etc. The total RNA was isolated from LPS matured DCs (positive control) and HIV infected DCs using Qiagen RNeasy Minikit. Agilent Quick-Amp Labelling kit (p/n 5190-0444) was used to synthesize the labeled cDNA from 3 ug of total RNA and further process the hybridized cDNA on the array. All the steps were carried out according to manufacturerM-bM-^@M-^Ys instructions (www.agilent.com/chem/dnamauals-protocol). The array slides were scanned immediately using high throughput Agilent scanner with SureScan technology. Agilent feature extraction software was used for normalization and statistical analysis,. Pathway and gene ontology analysis was done using Genespring GX v 10.0 and biointerpreter software. The experiments were performed on DCs cultured from two independent donors. The differential expression was considered if the Log 2 mean of at least -1 for the down regulated genes and +1 for the upregulated genes. We considered only the genes that were differentially regulated genes in both the donors.
2011-03-15 | E-GEOD-21017 | biostudies-arrayexpress
Project description:Increasing evidence indicates oncogenes and tumor suppressors not only influence cell fitness but can also control the immunophenotype of cells. Here, we examined how 34 commonly mutated genes in colorectal cancer (CRC) may influence the expression of 8 key immunomodulatory proteins. To do this, we employed a functional genomics approach utilizing Pro-Code/CRISPR libraries for high-dimensional analysis. We introduced a library of 102 Pro-Code/gRNA combinations, targeting each of the 34 genes, in CT26 cells, a CRC cell model, and measured the expression of each of the immunomodulatory proteins by CyTOF mass cytometry. Notably, cells carrying a Pro-Code/CRISPR targeting the Trp53 lost expression of the immune co-stimulatory molecule CD80. Validation confirmed that Trp53 knockout resulted in the loss of CD80 and that activation of P53, through DNA damage or stabilization, resulted in CD80 upregulation. P53 ChIP-seq identified the CD80 promoter as a direct target of P53. CD80 regulation by P53 was identified in other cells, including normal epithelial cells and macrophages. Functionally, CD80 reduction caused by P53 loss led to a reduced capacity for CRC to prime antigen-specific T cells. These studies establish CD80, a canonical co-stimulatory molecule, as a direct target of the tumor suppressor and DNA damage response gene, P53.
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Project description:Dendritic cells (DCs), professional antigen presenting cells, have demonstrated effective in controllingthe initial of innate immune, while CpG could improve the performance of immune system. To explorethe mechanism of CpG enhancing the immune response, we compared different stimulated mouse DCswith systemic approach microarrays. Analysis revealed 1840 differentially expressed genes in H9N2stimulated group, more than 1728 altered genes in inactive H9N2 group. Investigation also proved thatCpG/inactive H9N2 co-stimulation changed 2140 genes, more than that in H9N2 group, strongly demon-strated that CpG improved the performance of inactive H9N2 vaccination. Pathways analysis founded thatDCs response rapid to shift in their maturation state, which involved Toll-like receptor (TLR) pathwaysignificantly. Microarrays results were also verified by qRT-PCR with 14 elected representative genes. Fur-ther analysis proved that co-stimulatory molecules (CD40, CD80, CD86 and MHC-II), regulatory protein(IRF-7 and TRAF-6) and pro-inflammatory cytokines (IL-1, IL-6 and IL-12) were all changed and involvedin DCs maturation. At last we demonstrated TLR signalling pathway in chicken bone marrow-deriveddendritic cells (chBM-DCs) stimulated with CpG. The distinct transcriptional profiles of DCs pulsed withvarious stimuli expanded our understanding of how DCs respond and recognize influenza.
2012-10-11 | GSE41454 | GEO
Project description:DCs are localized under the mucosa of the lungs and the gastrointestinal tract, and therefore come into close contact with A. fumigatus germ tubes during early steps of infection as soon as fungi become invasive. For a more detailed insight into differentially regulated genes, whole genome microarray analysis was performed. On average, unstimulated DCs showed expression of about 13.500 genes (35% of all genes spotted on the chip). After 6h co-cultivation of DCs and live A. fumigatus germ tubes, 590 genes showed a 4fold altered gene expression, if normalizing data with VSN before. Therein, a wide range of immune response genes, including genes encoding for cytokines (IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-12p40, TNF-α), chemokines (CCL5, CCL20, CXCL10), immunorelevant receptors (TLR2, TLR4, PTX-3), as well as costimulatory molecules (CD40, CD80, CD83, CD86) were differentially regulated. Experiment Overall Design: Human DCs were generated from two independent, healthy blood donors. 5 x 106 DCs were either cultivated without fungi or together with 5 x 106 A. fumigatus germ tubes for 6h until isolation of total RNA.
2008-06-15 | E-GEOD-6965 | biostudies-arrayexpress
Project description:MET-altered human cancer cell lines including Hs746T (MET-mutated/amplified), H596 (MET-mutated) and H1993 (MET-amplified) cells were used. In microarray analysis, MET suppression using MET inhibitor or siRNAs up-regulated variable co-stimulatory molecules, including 4-1BBL, OX40L and CD70, and down-regulated variable co-inhibitory molecules. Among co-inhibitory molecules, PD-L1 was one of the most markedly down-regulated genes by MET suppression, which was validated at the mRNA and total/surface protein levels in Hs746T and H1993 cells. Consistently, MET activation by HGF treatment increased PD-L1 expression in H596 cells. Co-culture of human peripheral blood mononuclear cells (PBMC) with Hs746T cells suppressed IFNg production from PBMC, which was restored by an MET inhibitor or PD-L1 blockade. A significant positive correlation between MET and PD-L1 expression was observed in The Cancer Genome Atlas (TCGA) analysis for variable cancer types and immunohistochemistry for lung cancer. MET overexpression in PD-L1-high tumor exhibited decreased expressions of T-cell effector molecules in TCGA analysis for lung cancer. In summary, MET overexpression/activation is related to immunosuppressive phenotype and is involved in immune escape of tumor by PD-L1 up-regulation. MET-targeted therapy combined with immunotherapy could be a potential therapeutic strategy in MET-dependent cancer.
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Project description:West Nile virus (WNV) is a neurotropic flavivirus and the leading cause of mosquito-borne encephalitis in the United States. Recent studies in humans have found that dysfunctional T cell responses strongly correlate with development of severe WNV neuroinvasive disease. However, the contributions of human dendritic cells (DCs) in priming WNV-specific T cell immunity remains poorly understood. Here, we demonstrate that human monocyte derived DCs (moDCs) support productive viral replication following infection with a pathogenic strain of WNV. Antiviral effector gene transcription was strongly induced during the log-phase viral growth, while secretion of type I interferons (IFN) occurred with delayed kinetics. Activation of RIG-I like receptor (RLR) or type I IFN signaling prior to log-phase viral growth significantly diminished viral replication, suggesting that early activation of antiviral programs can block WNV infection. In contrast to the induction of antiviral responses, WNV infection did not promote transcription or secretion of pro-inflammatory (IL-6, GM-CSF, CCL3, CCL5, CXCL9) or T cell modulatory cytokines (IL-4, IL-12, IL-15). There was also minimal induction of molecules associated with antigen presentation and T cell priming, including the co-stimulatory molecules CD80, CD86, and CD40. Functionally, WNV-infected moDCs dampened allogenic CD4 and CD8 T cell activation and proliferation. Combined, we propose a model where WNV subverts human DC activation to compromise priming of WNV-specific T cell immunity.
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Project description:We performed microarray analysis of sCD40L-stimulated iDC to derive a signature of CD40 activation. Human monocytes from normal healthy donors were differentiated to iDCs with GM-CSF and IL4. FACS analysis demonstrated the immature status of these cells, illustrated by low expression of CD80, CD40, and CD86. We confirmed that sCD40L induces the maturation of DCs, characterized by higher expression of CD80, HLA-DR, CD86, CD83 and CD40 and secretion of pro-inflammatory cytokines at 24hr post-stimulation. Cells were harvested at 1, 3 and 24hr post-stimulation for microarray analysis.
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Project description:Hodgkin-like adult T-cell leukemia/lymphoma (ATLL) is a rare subtype of ATLL harboring human T cell lymphotropic virus type-1-infected Hodgkin-Reed-Sternberg (HRS)-like cells and small to medium CD4+ T cells, which histologically mimics classic Hodgkin lymphoma (CHL). CD30+ tumor cells or HRS cells are surrounded by CD4+ non-neoplastic T cells in a rosette-like manner in CHL. Interaction between HRS cells and surrounding CD4+ T cells is important for tumor microenvironment (TME) in CHL. Tumor microenvironment of Hodgkin-like ATLL remains unclear. Here, Digital Spatial Profiling was performed on Hodgkin-like ATLL to elucidate the interaction between HRS-like cells and CD4+ T cells in Hodgkin-like ATLL. We identified CD4+ T cells expressing co-stimulatory molecules, CD28 and inducible T cell co-stimulator (ICOS), in CD4+ T cells surrounding the HRS-like cells than in those apart from HRS-like cells. Immunohistochemistry was performed in 11 cases of Hodgkin-like ATLL, which detected distinct CD4+ T cells expressing CD28 in a rosette-like manner around HRS-like cells. HRS-like cells widely expressed CD80 and CD86, which suggested CD28-CD80/CD86 interaction was important in pathogenesis of Hodgkin-like ATLL. ICOS and immune checkpoint molecules, including T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed death-1 (PD-1) were also variably expressed in CD4+ T cells surrounding HRS-like cells. Our findings provide new insights into the tumor microenvironment of Hodgkin-like ATLL and implicate a new therapeutic strategy targeting these molecules.
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