Individual Liver Plasmacytoid Dendritic Cells Are Capable of Producing IFNa and Multiple Additional Cytokines During Chronic HCV Infection

Details

• Personal Author:
  Aloman C ; Branch AD ; Doyle EH ; El-Shamy A ; Eng F ; Fiel MI ; Florman SS ; Haydel B ; Kim S ; Klepper AL ; Rahman A ; Rocha C ; Schiano T
• Description:
  Plasmacytoid dendritic cells (pDCs) are "natural" interferon a (IFNa)-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 IFNa mRNA in HCV-infected livers, suggesting that pDCs may be incapable of producing IFNa. 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 IFNa in response TLR-7/8 stimulation. Liver pDCs secreted large quantities of IFNa (approx. 2 million molecules of IFNa/cell/hour) and produced more IFNa than PBMCs after stimulation, p = 0.0001. LMCs secreted >14-fold more IFNa than IFNlambda in 4 hours. Liver pDC frequency positively correlated with whole liver expression of "IFNa-response" pathway (R2 = 0.58, p = 0.007) and "monocyte surface" signature (R2 = 0.54, p = 0.01). Mass cytometry revealed that IFNa-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 IFNa 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. [Description provided by NIOSH]
• Subjects:
  Antigens Immune System Occupational Health Safety
• Keywords:
  Cytokines Hepatitis C Immune Reaction Immunology Liver Damage
• ISSN:
  1553-7374
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Illinois ; New York ; OSHA Region 2 ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  15
• Issue:
  7
• NIOSHTIC Number:
  nn:20068511
• Citation:
  PLoS Pathog 2019 Jul; 15(7):e1007935
• Contact Point Address:
  Andrea D. Branch, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
• Email:
  Andrea.Branch@mssm.edu
• Federal Fiscal Year:
  2019
• Performing Organization:
  Icahn School of Medicine at Mount Sinai, New York
• Peer Reviewed:
  True
• Start Date:
  20170701
• Source Full Name:
  PLoS Pathogens
• End Date:
  20210630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:58cdeea4faedfbd33d30d43ba00e802f17bfd8ab9d91ec90b62ff82b511baeae2d76a0cfad1d09d21157a70deb8c6d516e8eb3a34b2917534ee5a2ad9a5cbae8
• Download URL:
  https://stacks.cdc.gov/view/cdc/207127/cdc_207127_DS1.pdf
• File Type:
  [PDF - 4.53 MB ]