Immunoregulation by HCV-generated Myeloid Suppressor Cells

The hepatitis C virus (HCV) infects more than 200 million people worldwide and establishes chronic infection in 80% of these patients, resulting in chronic persistent liver inflammation and liver disease including most notably cirrhosis and hepatocellular carcinoma. HCV’s ability to establish persistent infection can be partly attributed to its immune evasion strategies, including the induction of a myeloid-derived suppressor cell (MDSCs) response.

As innate immune effectors, NK cells play an important role in controlling HCV infection and therefore suppressing chronic disease progression. IFN-γ production by liver NK cells likely suppresses virus replication in exposed hepatocytes and is important for the initiation of the adaptive immune response. However, following HCV infection, NK function is significantly impaired in chronic HCV patients compared to HCV patients who clear the infection. The cellular and molecular mechanisms to account for impaired NK function are not established.

In my research, I analyzed the interaction of human NK cells in vitro with CD33+ PBMCs following prior exposure of the CD33+ cells to HCV. We found that following co-culture of NK cells with HCV-conditioned CD33+ PBMCs, NK cell IFN-γ production is significantly inhibited while granzyme release by stimulated NK cells is normal. This suppression of NK cell-derived IFN-γ production is mediated by CD33+CD11bloHLA-DRloArg-1+ MDSCs. The suppression of IFN-γ production is reversed by L-arginine supplementation, consistent with L-arginine depletion as a result of MDSC arginse-1 activity. Moreover, unlike IFN-γ, granzyme B production was not affected by depletion of L-arginine. In addition, I have determined that the mTOR pathway is responsible for decreased IFN-γ translation. Taken together, these results suggest that HCV employs an immunoregulatory mechanism to alter NK cell metabolic state, which in turn inhibits one of their main effector functions, through the generation of suppressive myeloid cells. This further implies that the blockade of MDSCs’ suppressive effect on NK cells may be a potential therapeutic target to prevent chronic HCV infection and development of chronic liver diseases.