title: Myeloid suppressor cells induced by hepatitis C virus suppress T-cell responses through the production of reactive oxygen species.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Microbiology & Carter Immunology Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Tacke
authors.forename: Hai-Chon
authors.initials: HC
authors.lastname: Lee
authors.forename: Celeste
authors.initials: C
authors.lastname: Goh
authors.forename: Jeremy
authors.initials: J
authors.lastname: Courtney
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Polyak
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Rosen
authors.forename: Young S
authors.initials: YS
authors.lastname: Hahn
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D045744:Cell Line, Tumor; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism*; D063268:Sialic Acid Binding Ig-like Lectin 3; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation; D014758:Viral Core Proteins / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D017382:Reactive Oxygen Species; D063268:Sialic Acid Binding Ig-like Lectin 3; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus