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Individual liver plasmacytoid dendritic cells are capable of producing IFNα and multiple additional cytokines during chronic HCV infection.
Doyle, Erin Heather; Rahman, Adeeb; Aloman, Costica; Klepper, Arielle L; El-Shamy, Ahmed; Eng, Francis; Rocha, Chiara; Kim, Sang; Haydel, Brandy; Florman, Sander S; Fiel, M Isabel; Schiano, Thomas; Branch, Andrea D.
Afiliação
  • Doyle EH; Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
  • Rahman A; Human Immune Monitoring Core, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
  • Aloman C; Rush University Medical Center, Chicago, Illinois, United States of America.
  • Klepper AL; Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
  • El-Shamy A; Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
  • Eng F; Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
  • Rocha C; Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America.
  • Kim S; Department of Anesthesiology, The Mount Sinai Hospital, New York, New York, United States of America.
  • Haydel B; Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America.
  • Florman SS; Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America.
  • Fiel MI; Department of Pathology, The Mount Sinai Hospital, New York, New York, United States of America.
  • Schiano T; Recanati Miller Transplantation Institute, The Mount Sinai Hospital, New York, New York, United States of America.
  • Branch AD; Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
PLoS Pathog ; 15(7): e1007935, 2019 07.
Article em En | MEDLINE | ID: mdl-31356648
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Aged / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Aged / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2019 Tipo de documento: Article