Natural killer cells and hepatitis C: Natural killer p46 expression linked to antiviral and antifibrotic activity

N atural killer (NK) cells play an important role in innate immune response and are essential in the host’s first-line defense against viral infections. A major hallmark of NK cells is their ability to kill infected cells without requiring previous immunization and to produce large amounts of antiviral effector cytokines, including interferon gamma (IFN-c) and tumor necrosis factor alpha (TNF-a). NK cells also play an important role in the priming and regulation of adaptive immune responses. For example, NK cells can regulate T-cell responses by lysing virusinfected antigen-presenting cells or by cytolytically eliminating activated CD4 T cells that affect CD8 T-cell function and exhaustion, as has been recently demonstrated in the lymphocytic choriomeningitis virus mouse model. Accordingly, in that model, NK-cell depletion causes enhanced T-cell immunity that may lead to rapid virus control and prevention of chronic infection. Based on to the intensity of CD56 expression, NK cells can be divided into two functional different subsets. CD56 NK cells represent approximately 90% of the circulating NK-cell population and predominantely mediate cytotoxic effector functions. CD56 NK cells contribute up to 10% of the peripheral blood NK-cell population and their primary function is cytokine production. However, recent studies have challenged this simple dichotomy by showing that CD56, as well as CD56, cells are capable of exerting both functions. NK-cell activation and function is tightly regulated by multiple activating and inhibitory receptors. NK receptors include (1) the killer cell immunoglobulin-like receptors (KIRs) that recognize human leukocyte antigen (HLA) class I molecules, (2) the C-type lectin receptors, including the activating receptors, NKG2C, NKG2D, and NKG2E, and the inhibitory receptor, NKG2A, and (3) the activating natural cytotoxicity receptors, such as NKp30, NKp44, and NKp46. In hepatitis C virus (HCV) infection, the essential role of NK cells has been shown in several studies. For example, Khakoo et al. found that KIR2DL3, an inhibitory NK-cell receptor, and its HLA-C1 ligand directly influence the outcome of HCV infection. During acute infection, NK cells are activated, irrespective of the later outcome of infection, and they produce higher amounts of IFN-c and are more cytotoxic, compared to NK cells obtained from healthy controls. Peak NK-cell activity either precedes or coincides with peak T-cell responses, supporting an indirect role of NK cells in priming and regulating adaptive immune responses. During chronic HCV infection, pertubations in NK-cell frequency, phenotype, and function have been reported, as reviewed elsewhere. Indeed, peripheral blood NK-cell frequencies are reduced in chronic HCV infection, compared to healthy individuals. In addition, an impaired production of the TH1 polarizing cytokine, IFN-c, and an increased production of immunoregulatory cytokines, such as interleukin (IL)-10 and transforming growth factor beta, has been reported. In contrast, cytotoxicity of NK cells is increased and correlates with the degree of liver inflammation. This polarization toward cytotoxicity may be induced by IFN-a. Given their important role in the regulation of NK cells, several studies have analyzed the expression of inhibitory and activating receptors on NK cells during acute and chronic HCV infection. Most, but not all, of these studies have revealed an increase in the expression of the inhibitory receptor, NKG2A, and the activating receptors, such as NKp30, NKp44, and NKp46. NKp46 is a particularly interesting molecule. It is considered to be the main activating NK-cell receptor and has been shown to be involved in tumor eradication and the killing of virus-infected cells by interacting with viral proteins, and up-regulation of NKp46 in response to IFN-c can predict a sustained virological response (SVR) in chronic HCV infection. Abbreviations: AA, African Americans; CA, Caucasian Americans; HCV, hepatitis C virus; HLA, human leukocyte antigen; HSCs, hepatic stellate cells; IFN-c, interferon gamma; KIRs, killer cell immunoglobulin-like receptors; IL, interleukin; NK, natural killer; SVR, sustained virological response; TNF-a, tumor necrosis factor alpha; Address reprint requests to: Robert Thimme, M.D., Department of Medicine II, University Hospital Freiburg, Hugstter Strasse 55, Freiburg 79106, Germany. E-mail: Robert.thimme@uniklinik-freiburg.de; fax: þ49 761 270 33170. CopyrightVC 2012 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.25858 Potential conflict of interest: Nothing to report.