Individual liver plasmacytoid dendritic cells are capable of producing IFNα and multiple additional cytokines during chronic HCV infection

被引：14

作者：

Doyle, Erin Heather ^{[1
]}

Rahman, Adeeb ^{[2
]}

Aloman, Costica ^{[3
]}

Klepper, Arielle L. ^{[1
]}

El-Shamy, Ahmed ^{[1
]}

Eng, Francis ^{[1
]}

Rocha, Chiara ^{[4
]}

Kim, Sang ^{[5
]}

Haydel, Brandy ^{[4
]}

Florman, Sander S. ^{[4
]}

Fiel, M. Isabel ^{[6
]}

Schiano, Thomas ^{[4
]}

Branch, Andrea D. ^{[1
]}

机构：

[1] Icahn Sch Med Mt Sinai, Div Liver Dis, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Human Immune Monitoring Core, New York, NY 10029 USA

[3] Rush Univ, Med Ctr, Chicago, IL 60612 USA

[4] Mt Sinai Hosp, Recanati Miller Transplantat Inst, New York, NY 10029 USA

[5] Mt Sinai Hosp, Dept Anesthesiol, New York, NY 10029 USA

[6] Mt Sinai Hosp, Dept Pathol, New York, NY 10029 USA

来源：

PLOS PATHOGENS | 2019年 / 15卷 / 07期

关键词：

HEPATITIS-C VIRUS; INTERFERON-LAMBDA; GENE-EXPRESSION; RESPONSES; DISTINCT; BLOOD; RNA;

D O I：

10.1371/journal.ppat.1007935

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Plasmacytoid dendritic cells (pDCs) are "natural" interferon alpha (IFN alpha)-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 alpha mRNA in HCV-infected livers, suggesting that pDCs may be incapable of producing IFN alpha. 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 alpha in response TLR-7/8 stimulation. Liver pDCs secreted large quantities of IFN alpha (similar to 2 million molecules of IFN alpha/cell/hour) and produced more IFN alpha than PBMCs after stimulation, p = 0.0001. LMCs secreted >14-fold more IFN alpha than IFN lambda in 4 hours. Liver pDC frequency positively correlated with whole liver expression of IFN alpha-response pathway (R-2 = 0.58, p = 0.007) and monocyte surface signature (R-2 = 0.54, p = 0.01). Mass cytometry revealed that IFN alpha-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 alpha 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.

引用

页数：22