Myeloid suppressor cells induced by hepatitis C virus suppress T-cell responses through the production of reactive oxygen species

Hepatology. 2012 Feb;55(2):343-53. doi: 10.1002/hep.24700.

Abstract

Impaired T-cell responses in chronic hepatitis C virus (HCV) patients have been reported to be associated with the establishment of HCV persistent infection. However, the mechanism for HCV-mediated T-cell dysfunction is yet to be defined. Myeloid-derived suppressor cells (MDSCs) play a pivotal role in suppressing T-cell responses. In this study we examined the accumulation of MDSCs in human peripheral blood mononuclear cells (PBMCs) following HCV infection. We found that CD33(+) mononuclear cells cocultured with HCV-infected hepatocytes, or with HCV core protein, suppress autologous T-cell responses. HCV core-treated CD33(+) cells exhibit a CD14(+) CD11b(+/low) HLADR(-/low) phenotype with up-regulated expression of p47(phox) , a component of the NOX2 complex critical for reactive oxygen species (ROS) production. In contrast, immunosuppressive factors, arginase-1 and inducible nitric oxide synthase (iNOS), were not up-regulated. Importantly, treatment with an inactivator of ROS reversed the T-cell suppressive function of HCV-induced MDSCs. Lastly, PBMCs of chronic HCV patients mirror CD33(+) cells following treatment with HCV core where CD33(+) cells are CD14(+) CD11b(+) HLADR(-/low) , and up-regulate the expression of p47(phox).

Conclusion: These results suggest that HCV promotes the accumulation of CD33(+) MDSC, resulting in ROS-mediated suppression of T-cell responsiveness. Thus, the accumulation of MDSCs during HCV infection may facilitate and maintain HCV persistent infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigen-Presenting Cells / immunology*
  • Antigen-Presenting Cells / metabolism
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Cell Line, Tumor
  • Hepatitis C, Chronic / immunology*
  • Hepatitis C, Chronic / metabolism
  • Hepatocytes / immunology
  • Humans
  • Lymphocyte Activation
  • Phenotype
  • Reactive Oxygen Species / metabolism*
  • Sialic Acid Binding Ig-like Lectin 3
  • T-Lymphocytes / immunology*
  • Up-Regulation
  • Viral Core Proteins / physiology*

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD33 protein, human
  • Reactive Oxygen Species
  • Sialic Acid Binding Ig-like Lectin 3
  • Viral Core Proteins
  • nucleocapsid protein, Hepatitis C virus