Functional changes of natural killer cells in the early phase of hepatitis C virus infection

Abstract

[한글]

[영문]Natural killer (NK) cells play important roles in the containment of virus infectionsthrough killing infected cells and suppressing viral replication and in thedevelopment of adaptive immune responses by promoting maturation of dendriticcells and differentiation of helper T cells. If NK cells are inhibited during theincubation period of virus infection, their functional impairment will, therefore,result in inappropriate confinement of viruses, suboptimal priming anddifferentiation of T cells, and a long symptom-free incubation period. Hepatitis C virus (HCV) infection may inhibit NK cells in the early course ofinfection, because the incubation period of hepatitis C persists for 8-12 weeks inthe absence of detectable symptoms. Since it has been reported that NK cellfunction is intact after direct exposure to cell-free HCV virions, the long incubationphase may be due to the inhibition of NK cells by HCV-infected hepatocytes, inwhich HCV induces changes that may inhibit NK cell function. To investigate whether HCV infection modulates NK cell function, NK cellswere subjected to interaction with HCV-infected cells. HCV-permissive humanhepatoma cell lines were infected with cell-culture-generated HCV virions andcocultured with primary human NK cells. When the infected cells contacted withNK cells three days post infection, they significantly inhibited degranulationactivity of NK cells. It means that NK cells’ ability to confine HCV at the site ofinitial infection through killing infected cells was significantly reduced. This isconsistent with the results from chimpanzee studies that show no serum alanineaminotransferase increase but increase of serum HCV RNA titers during the earlyincubation phase of HCV infection. Furthermore, the interaction between NK cellsand HCV-infected cells brought significantly reduced expression of NKG2D, anactivating NK receptor, on the surface of NK cells. NKG2D downregulationcoincided with the reduced degranulation activity of NK cells, and the lowcytotoxicity was chiefly associated with NKG2D downregulation on the CD56dimNK subset. Both degranulation of NK cells and NKG2D expression on NK cellswere reconstituted after 24-hour rest in the absence of interaction with HCVinfectedcells. Interferon (IFN)-γ secretion by interleukin (IL)-12-stimulated NKcells was also diminished after coculture with HCV-infected cells. Decreased IFN-γ secretion was consistent with reduced degranulation by and decreased NKG2Dexpression on NK cells interacted with HCV-infected cells. In conclusion, NK cell function is modulated after interplay with HCV-infectedcells in the early phase of infection in vitro. The functional impairment depends, atleast in part, on the downregulation of NKG2D expression on the surface of NKcells. The functional changes of CD56dim NK cells may explain the rise of HCVreplication in the absence of immune-mediated killing of hepatocytes during theearly incubation phase of HCV infection in vivo. In addition, the reduction of IFN-γsecretion by NK cells interacted with HCV-infected cells may hold a clue to themechanism of suboptimal development of helper T cells and cytotoxic T cells inthe HCV infection.