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

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. (HEPATOLOGY 2012)