Effect of HIV infection on co-stimulatory capacity of dendritic cells
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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.
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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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