HCV impairs human T cell responses via MDSC induction. (154.2)

Abstract

Abstract Hepatitis C virus (HCV) is highly efficient in establishing persistent infection, which leads to the development of chronic liver disease and hepatocellular carcinoma. Impaired T cell responses with reduced IFN-γ production have been reported to be associated with HCV persistent infection. Extracellular HCV core is a viral factor known to cause HCV-induced T cell impairment via its suppressive effect on the activation and induction of pro-inflammatory responses by antigen presenting cells (APCs). Recently, myeloid derived suppressor cells (MDSC) have been shown to be crucial regulators of T cell responses. In this report we examine the accumulation of MDSCs in human PBMCs following exposure to extracellular core. We show that HCV core induces the activation of STAT3 in human APCs. Importantly, co-cuture of HCV core-treated CD33+ APCs with CD4 T cells suppresses autologous CD4 T cell proliferation and IFN-γ production in response to TCR stimulation. This suppression is partially rescued by STAT3 inhibitor WP1066, as well as by reactive oxygen species (ROS) inhibitor, catalase. In contrast, inhibitors to arginase-1 and iNOS do not affect T cell responsiveness. These results suggest that HCV core -mediated STAT3 activation promotes in the accumulation of CD33+ MDSC, resulting in ROS-mediated suppression of T cell responsiveness. The accumulation of these MDSC may facilitate the establishment of HCV chronic infection.