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Individual liver plasmacytoid dendritic cells are capable of producing IFNα and multiple additional cytokines during chronic HCV infection.
- Source :
-
PLoS pathogens [PLoS Pathog] 2019 Jul 29; Vol. 15 (7), pp. e1007935. Date of Electronic Publication: 2019 Jul 29 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Plasmacytoid dendritic cells (pDCs) are "natural" interferon α (IFNα)-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 IFNα mRNA in HCV-infected livers, suggesting that pDCs may be incapable of producing IFNα. 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 IFNα in response TLR-7/8 stimulation. Liver pDCs secreted large quantities of IFNα (~2 million molecules of IFNα/cell/hour) and produced more IFNα than PBMCs after stimulation, p = 0.0001. LMCs secreted >14-fold more IFNα than IFNλ in 4 hours. Liver pDC frequency positively correlated with whole liver expression of "IFNα-response" pathway (R2 = 0.58, p = 0.007) and "monocyte surface" signature (R2 = 0.54, p = 0.01). Mass cytometry revealed that IFNα-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 IFNα 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.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Aged
Antigens, CD1 blood
Antigens, CD1 metabolism
Antigens, Surface blood
Antigens, Surface metabolism
Chemokines biosynthesis
Dendritic Cells classification
Dendritic Cells pathology
Female
Glycoproteins blood
Glycoproteins metabolism
Hepatitis C, Chronic blood
Hepatitis C, Chronic pathology
Humans
Interferon-alpha blood
Interferon-gamma biosynthesis
Interferon-gamma blood
Liver immunology
Liver pathology
Male
Middle Aged
Thrombomodulin
Cytokines biosynthesis
Dendritic Cells immunology
Hepatitis C, Chronic immunology
Interferon-alpha biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 15
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 31356648
- Full Text :
- https://doi.org/10.1371/journal.ppat.1007935