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+/lowHLADR−/low phenotype with up-regulated expression of p47phox, 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 p47phox. 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.

Myeloid Derived Suppressor Cells and Their Role in Diseases

“…However, upon treatment with IFN-γ and IL-4, they could eliminate the parasites in a NO-dependent manner. A similar expansion of MDSCs was also seen in Hepatitis C virus (HCV) infections in humans, where T-cell proliferation was suppressed through a ROSmediated mechanism [86].…”

Contact-Dependent Depletion of Hydrogen Peroxide by Catalase Is a Novel Mechanism of Myeloid-Derived Suppressor Cell Induction Operating in Human Hepatic Stellate Cells

“…Our findings both in primary human HSC and the LX-2 cell line provide evidence that This may explain why HUH7 cells are unable to induce MDSC despite expressing high levels of catalase because CD44 is absent from noninfected HUH7 cells (38,39). Of note, the concentration of purified catalase used in our monocyte cultures is only likely to be achieved locally when cells are in close proximity (see Fig.…”

Expression and Clinical Significance of Myeloid Derived Suppressor Cells in Chronic Hepatitis B Patients

“…It has been reported that MDSCs presented in viral infectious diseases, autoimmune diseases, tumor, and parasitic infections diseases and inhibited the T cell proliferation (Greten et al, 2011;Tacke et al, 2012;Vollbrecht et al, 2012). However; MDSCs expression about the mechanism and course of the disease for chronic HBV patients was limited.…”

“…hepatitis C Viral (HCV) and Acquired Immune Deficiency Syndrome (AIDS) (Tacke et al, 2012;Vollbrecht et al, 2012;Cai et al, 2013;Qin et al, 2013). On the other hand, complications of chronic hepatitis B (CHB), e.g.…”