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| Status |
Public on Jul 10, 2019 |
| Title |
Individual liver plasmacytoid dendritic cells are capable of producing IFNa and multiple additional cytokines during chronic HCV infection [exp1] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Plasmacytoid dendritic cells (pDCs) are ÒnaturalÓ interferon _ (IFN_)-producing cells. Despite their importance to antiviral defense, autoimmunity, and ischemic liver graft injury, because DC subsets are rare and heterogeneous, basic questions about liver pDC function and capacity to make cytokines remain unanswered. Previous investigations failed to consistently detect IFN_ mRNA in HCV-infected livers, suggesting that pDCs may be incapable of producing IFN_. We used a combination of molecular, biochemical, cytometric, and high-dimensional techniques to analyze DC frequencies/functions in liver and peripheral blood mononuclear cells (PBMCs) of hepatitis C virus (HCV)-infected patients, to examine correlations between DC function and gene expression of matched whole liver tissue and liver mononuclear cells (LMCs), and to determine if pDCs can produce multiple cytokines. T cells often produce multiple cytokines/chemokines but until recently technical limitations have precluded tests of polyfunctionality in individual pDCs. Mass cytometry (CyTOF) revealed that liver pDCs are the only LMC that produces detectable amounts of IFN_ in response TLR-7/8 stimulation. Liver pDCs secreted large quantities of IFN_ (~2 million molecules of IFN_/cell/hour) and produced more IFN_ than PBMCs after stimulation, p=0.0001. LMCs secreted >14-fold more IFN_ than IFN_ in 4 hours. Liver pDC frequency positively correlated with whole liver expression of ÒIFN_-responseÓ pathway (R2=0.58, p=0.007) and Òmonocyte surfaceÓ signature (R2=0.54, p=0.01). Mass cytometry revealed that IFN_-producing pDCs were highly polyfunctional; >90% also made 2-4 additional cytokines/chemokines of our test set of 10. Liver BDCA1 DCs, but not BDCA3 DCs, were similarly polyfunctional. pDCs from a healthy liver were also polyfunctional. Our data show that liver pDCs retain the ability to make abundant IFN_ during chronic HCV infection and produce many other immune modulators. Polyfunctional liver pDCs are likely to be key drivers of inflammation and immune activation during chronic HCV infection.
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| Overall design |
Total RNA from 55 samples isolated from liver or blood mononuclear cells either ex vivo or stimulated with media, Poly I:C, LPS, or R848
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| Contributor(s) |
Doyle EH |
| Citation missing |
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| |
| Submission date |
Jul 09, 2019 |
| Last update date |
Jul 10, 2019 |
| Contact name |
Erin Heather Doyle |
| E-mail(s) |
erin.doyle@mssm.edu
|
| Organization name |
Icahn School of Medicine at Mount Sinai
|
| Department |
Liver
|
| Street address |
1425 Madison Ave
|
| City |
New York |
| State/province |
New York |
| ZIP/Postal code |
10029 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL10904 |
Illumina HumanHT-12 V4.0 expression beadchip (gene symbol) |
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| Samples (55)
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| This SubSeries is part of SuperSeries: |
| GSE134042 |
Individual liver plasmacytoid dendritic cells are capable of producing IFNa and multiple additional cytokines during chronic HCV infection |
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| Relations |
| BioProject |
PRJNA553545 |
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