A View to Natural Killer Cells in Hepatitis C

Abstract

See “Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C,” by Ahlenstiel G, Edlich B, Hogdal LJ, et al, on page 1231. See “Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C,” by Ahlenstiel G, Edlich B, Hogdal LJ, et al, on page 1231. Natural killer (NK) cells are among the earliest effector populations of the innate immune response. They constitute 5%–15% of peripheral blood lymphocytes and 30%–50% of intrahepatic lymphocytes.1Doherty D.G. O'Farrelly C. Innate and adaptive lymphoid cells in the human liver.Immunol Rev. 2000; 174: 5-20Google Scholar Early during infections, NK cells kill infected cells via direct release of perforin and granzymes or through tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated killing. Furthermore, they produce cytokines (eg, interferon [IFN]-γ and TNF-α) that can directly inhibit viral replication and prime the adaptive immune response. NK cells interact with dendritic cells (DCs) in a reciprocal manner, leading to increased NK cell activation as well as maturation of DCs.2Moretta L. Ferlazzo G. Bottino C. et al.Effector and regulatory events during natural killer-dendritic cell interactions.Immunol Rev. 2006; 214: 219-228Google Scholar In addition, NK cells can eliminate immature DCs and limit antigen presentation. Hence, NK–DC interaction is crucial to both innate and adaptive immune regulation. Activation of NK cells is governed by a balance between activating and inhibitory receptors. Activating receptors include C-type lectin-like receptors (NKG2C, NKG2D, and NKG2E), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), and CD16 while the main inhibitory receptors are the killer cell immunoglobulin-like receptors (KIR) and the C-type lectin like receptor (NKG2A).2Moretta L. Ferlazzo G. Bottino C. et al.Effector and regulatory events during natural killer-dendritic cell interactions.Immunol Rev. 2006; 214: 219-228Google Scholar NK cells are CD3−, CD56+, and are divided into 2 main subsets according to the intensity of CD56 expression on cell surface: Differentiated CD56dim and the less mature CD56bright. CD56dim cells were originally classified as cytotoxic, whereas CD56bright cells were considered cytokine producers,2Moretta L. Ferlazzo G. Bottino C. et al.Effector and regulatory events during natural killer-dendritic cell interactions.Immunol Rev. 2006; 214: 219-228Google Scholar but recent studies have demonstrated that the 2 subsets are capable of both functions.3De Maria A. Bozzano F. Cantoni C. et al.Revisiting human natural killer cell subset function revealed cytolytic CD56(dim)CD16+ NK cells as rapid producers of abundant IFN-gamma on activation.Proc Natl Acad Sci U S A. 2011; 108: 728-732Google Scholar, 4Fauriat C. Long E.O. Ljunggren H.G. et al.Regulation of human NK-cell cytokine and chemokine production by target cell recognition.Blood. 2010; 115: 2167-2176Google Scholar A subset of dysfunctional CD56−, CD16+ NK cells also accumulate during chronic viral infections with hepatitis C virus (HCV) or HIV.5Alter G. Teigen N. Davis B.T. et al.Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection.Blood. 2005; 106: 3366-3369Google Scholar, 6Gonzalez V.D. Falconer K. Bjorkstrom N.K. et al.Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: correlation with outcome of pegylated IFN-alpha and ribavirin treatment.J Immunol. 2009; 183: 6612-6618Google Scholar, 7Mavilio D. Lombardo G. Benjamin J. et al.Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals.Proc Natl Acad Sci U S A. 2005; 102: 2886-2891Google Scholar Furthermore, a new subset of NK cells was described as major producers of interleukin (IL)-22,8Colonna M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity.Immunity. 2009; 31: 15-23Google Scholar a cytokine with hepatoprotective properties.9Zenewicz L.A. Yancopoulos G.D. Valenzuela D.M. et al.Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation.Immunity. 2007; 27: 647-659Google Scholar Given their high abundance in the liver, NK cells have recently become a topic of intense investigation in the context of HCV infection and therapy. The importance of NK cells during HCV infection was underscored by genetic studies demonstrating that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of HCV infection in individuals homozygous for these genes.10Khakoo S.I. Thio C.L. Martin M.P. et al.HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection.Science. 2004; 305: 872-874Google Scholar Several recent studies have demonstrated that NK cells are activated during acute HCV infection irrespective of subsequent virologic outcome toward spontaneous resolution or chronic infection.11Amadei B. Urbani S. Cazaly A. et al.Activation of natural killer cells during acute infection with hepatitis C virus.Gastroenterology. 2010; 138: 1536-1545Google Scholar, 12Alter G. Jost S. Rihn S. et al.Reduced frequencies of NKp30+NKp46+, CD161+, and NKG2D+ NK cells in acute HCV infection may predict viral clearance.J Hepatol. 2010; Google Scholar, 13Pelletier S. Drouin C. Bedard N. et al.Increased degranulation of natural killer cells during acute HCV correlates with the magnitude of virus-specific T cell responses.J Hepatol. 2010; 53: 805-816Abstract Full Text Full Text PDF Scopus (85) Google Scholar This activation was greatest among KIR2DL3-expressing NK cells and was associated with modulations of NKG2D, NKp30, and NKp46 expression.11Amadei B. Urbani S. Cazaly A. et al.Activation of natural killer cells during acute infection with hepatitis C virus.Gastroenterology. 2010; 138: 1536-1545Google Scholar, 12Alter G. Jost S. Rihn S. et al.Reduced frequencies of NKp30+NKp46+, CD161+, and NKG2D+ NK cells in acute HCV infection may predict viral clearance.J Hepatol. 2010; Google Scholar In addition, NK cells were more polarized toward degranulation, a surrogate marker of cytotoxicity, and enhanced TRAIL expression rather than cytokine production during acute13Pelletier S. Drouin C. Bedard N. et al.Increased degranulation of natural killer cells during acute HCV correlates with the magnitude of virus-specific T cell responses.J Hepatol. 2010; 53: 805-816Abstract Full Text Full Text PDF Scopus (85) Google Scholar and chronic HCV infection.14Oliviero B. Varchetta S. Paudice E. et al.Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections.Gastroenterology. 2009; 137: 1151-1160Google Scholar, 15Ahlenstiel G. Titerence R.H. Koh C. et al.Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner.Gastroenterology. 2010; 138: 325-335Google Scholar This cytotoxic effect was activated by low doses of IFN-α.15Ahlenstiel G. Titerence R.H. Koh C. et al.Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner.Gastroenterology. 2010; 138: 325-335Google Scholar During acute hepatitis C, peak NK cell activity either preceded or coincided with peak T-cell responses and degranulation of NK cells correlated with the magnitude of HCV-specific T-cell responses, suggesting an indirect role for NK cells in priming adaptive immunity.13Pelletier S. Drouin C. Bedard N. et al.Increased degranulation of natural killer cells during acute HCV correlates with the magnitude of virus-specific T cell responses.J Hepatol. 2010; 53: 805-816Abstract Full Text Full Text PDF Scopus (85) Google Scholar During chronic HCV infection, NK cells remain activated, express increased levels of NKG2A and CD69, and display normal or increased cytotoxicity (reviewed in Cheent and Khakoo16Cheent K. Khakoo S.I. Natural killer cells and hepatitis C: action and reaction.Gut. 2011; 60: 268-278Google Scholar). This activation correlates with the degree of liver inflammation measured by increased serum alanine aminotransferase (ALT)14Oliviero B. Varchetta S. Paudice E. et al.Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections.Gastroenterology. 2009; 137: 1151-1160Google Scholar, 15Ahlenstiel G. Titerence R.H. Koh C. et al.Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner.Gastroenterology. 2010; 138: 325-335Google Scholar or Metavir activity and fibrosis score.17Bonorino P. Ramzan M. Camous X. et al.Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C.J Hepatol. 2009; 51: 458-467Google Scholar Oliviero et al14Oliviero B. Varchetta S. Paudice E. et al.Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections.Gastroenterology. 2009; 137: 1151-1160Google Scholar have reported an inverse correlation between NKG2D and liver inflammation. In addition, Bonorino et al17Bonorino P. Ramzan M. Camous X. et al.Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C.J Hepatol. 2009; 51: 458-467Google Scholar have reported a positive correlation between NKG2A expression and necroinflammatory score and an inverse correlation with viral load. NK cells may also exhibit an altered cytokine profile that can contribute to viral persistence. For example, NK cells from HCV-infected patients were shown to produce less Th1 polarizing cytokine IFN-γ and more immunoregulatory cytokines IL-10 and TGF-β.14Oliviero B. Varchetta S. Paudice E. et al.Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections.Gastroenterology. 2009; 137: 1151-1160Google Scholar, 18Jinushi M. Takehara T. Tatsumi T. et al.Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection.J Immunol. 2004; 173: 6072-6081Crossref Scopus (185) Google Scholar, 19De Maria A. Fogli M. Mazza S. et al.Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients.Eur J Immunol. 2007; 37: 445-455Google Scholar It is not clear whether this altered cytokine profile is a compensatory response to dampen the ongoing inflammation in the liver or is rather promoted by the increase in liver resident, IL-10–producing T cells. Intrahepatic NK cells also express higher levels of activating receptors and TRAIL than peripheral NK cells (reviewed in Mondelli et al20Mondelli M.U. Varchetta S. Oliviero B. Natural killer cells in viral hepatitis: facts and controversies.Eur J Clin Invest. 2010; 40: 851-863Google Scholar). However, their function has not been extensively studied. In considering a role for NK cells in HCV therapy, NK cells are strongly activated by type I IFNs, including IFN-α,21Biron C.A. Nguyen K.B. Pien G.C. et al.Natural killer cells in antiviral defense: function and regulation by innate cytokines.Annu Rev Immunol. 1999; 17: 189-220Google Scholar a major component of HCV therapy that remain in the newer regimen including the direct-acting antivirals.22Ciesek S. Manns M.P. Hepatitis in 2010: the dawn of a new era in HCV therapy.Nat Rev Gastroenterol Hepatol. 2011; 8: 69-71Google Scholar IFN-α is ineffective in ∼50% of infected individuals and the host factors contributing to or predicting the outcome of therapy are poorly understood. Mathematical modeling suggested a 2-phase model for IFN-α–mediated HCV clearance from plasma.23Layden T.J. Mika B. Wiley T.E. Hepatitis C kinetics: mathematical modeling of viral response to therapy.Semin Liver Dis. 2000; 20: 173-183Google Scholar The first early phase lasts for approximately 48 hours, is characterized by rapid decline of plasma viral load, and is thought to reflect inhibition of viral replication by IFN-α. The decline in viral load during this phase is a strong predictor of early virologic response (EVR) and the outcome of therapy.24Parruti G. Polilli E. Sozio F. et al.Rapid prediction of sustained virological response in patients chronically infected with HCV by evaluation of RNA decay 48h after the start of treatment with pegylated interferon and ribavirin.Antiviral Res. 2010; 88: 124-127Google Scholar The second, slower phase is much longer and is suggested to represent immune-mediated elimination of infected hepatocytes. IFN-α treatment does not induce de novo HCV-specific T-cell responses, but it can preserve HCV-specific memory T cells if started early.25Badr G. Bedard N. Abdel-Hakeem M.S. et al.Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells.J Virol. 2008; 82: 10017-10031Google Scholar Because NK cells are rapidly activated by IFN-α, their activation early during therapy could contribute to viral clearance. In this issue of Gastroenterology, Ahlenstiel et al26Ahlenstiel G. Edlich B. Hogdal L.J. et al.Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C.Gastroenterology. 2011; 141: 1231-1239Google Scholar studied the activation and function of NK cells in peripheral blood at very early time points (6, 24, and 48 hours), representing the first phase of viral clearance after initiation of IFN-α treatment. They show that NK cells are activated within 6 hours of treatment initiation, up-regulating several NK cell–activating receptors (NKG2D, NKp30, CD16) and down-regulating NKG2C and 2B4 as well as the inhibitory receptors SIGLEC7 and NKG2A. Peripheral NK cells also showed increased cytotoxicity as measured by degranulation and TRAIL expression at 24 hours. This activation was sustained for 2 weeks in individuals who exhibited an EVR, but declined within 1 week in a control nonresponders group (a retreatment group with previous nonresponse to IFN therapy). Importantly, they also performed a cross-sectional comparison of intrahepatic NK cell subsets in patients who underwent liver biopsy at either baseline (before therapy) or 6 hours after IFN-α administration. A similar activation of intrahepatic NK cells was observed at 6 hours. There are several important aspects to this study. First, this is the first study to examine NK cell activation in peripheral blood and liver at such an early time point within 6–48 hours after treatment initiation. Second, although exogenous high-dose IFN-α is known to enhance NK cell polarization toward cytotoxicity27Par G. Rukavina D. Podack E.R. et al.Decrease in CD3-negative-CD8dim(+) and Vdelta2/Vgamma9 TcR+ peripheral blood lymphocyte counts, low perforin expression and the impairment of natural killer cell activity is associated with chronic hepatitis C virus infection.J Hepatol. 2002; 37: 514-522Google Scholar and TRAIL expression28Stegmann K.A. Bjorkstrom N.K. Veber H. et al.Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection.Gastroenterology. 2010; 138: 1885-1897Google Scholar during the first week of treatment, the current study shows that this occurs as early as within hours in vivo. Third, previous studies demonstrated that NK cell frequency in the liver29Yamagiwa S. Matsuda Y. Ichida T. et al.Sustained response to interferon-alpha plus ribavirin therapy for chronic hepatitis C is closely associated with increased dynamism of intrahepatic natural killer and natural killer T cells.Hepatol Res. 2008; 38: 664-672Google Scholar as well as NK cell cytotoxicity in peripheral blood were higher at the end of IFN-α–based therapy in patients who achieved sustained virologic response than nonresponders.27Par G. Rukavina D. Podack E.R. et al.Decrease in CD3-negative-CD8dim(+) and Vdelta2/Vgamma9 TcR+ peripheral blood lymphocyte counts, low perforin expression and the impairment of natural killer cell activity is associated with chronic hepatitis C virus infection.J Hepatol. 2002; 37: 514-522Google Scholar, 30Bonavita M.S. Franco A. Paroli M. et al.Normalization of depressed natural killer activity after interferon-alpha therapy is associated with a low frequency of relapse in patients with chronic hepatitis C.Int J Tissue React. 1993; 15: 11-16Google Scholar In the current study, the induction of NK cytotoxicity at very early time points correlated with the first-phase (48 hours) virologic response and EVR. The effect on long-term sustained virologic response could not be examined because not all patients completed therapy. The role of NK cells in determining the final outcome of HCV therapy requires further investigation, particularly with the inclusion of newer direct antivirals. Fourth, there was a decrease in the circulating frequency of NK cells expressing the liver homing chemokine receptors CXCR3+ and CCR5+, and slight increase in serum ALT at 24 hours after treatment initiation. These findings are consistent with increased killing of hepatocytes by activated intrahepatic NK cells or increased NK cells migrating to the liver, although such interactions including NK cell homing to the liver cannot be directly demonstrated in human studies. NK cells have been shown to control HCV replication via IFN-γ secretion in vitro31Wang S.H. Huang C.X. Ye L. et al.Natural killer cells suppress full cycle HCV infection of human hepatocytes.J Viral Hepat. 2008; 15: 855-864Google Scholar, 32Crotta S. Brazzoli M. Piccioli D. et al.Hepatitis C virions subvert natural killer cell activation to generate a cytokine environment permissive for infection.J Hepatol. 2010; 52: 183-190Abstract Full Text Full Text PDF Scopus (58) Google Scholar as well as in vivo after adoptive transfer of NK/NKT cells after liver transplantation.33Ohira M. Ishiyama K. Tanaka Y. et al.Adoptive immunotherapy with liver allograft-derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice.J Clin Invest. 2009; 119: 3226-3235Google Scholar Whereas NK cells from chronically HCV-infected patients display reduced IFN-γ production,14Oliviero B. Varchetta S. Paudice E. et al.Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections.Gastroenterology. 2009; 137: 1151-1160Google Scholar, 15Ahlenstiel G. Titerence R.H. Koh C. et al.Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner.Gastroenterology. 2010; 138: 325-335Google Scholar, 20Mondelli M.U. Varchetta S. Oliviero B. Natural killer cells in viral hepatitis: facts and controversies.Eur J Clin Invest. 2010; 40: 851-863Google Scholar the current study from Ahlenstiel et al suggests that cytotoxicity is the major mechanism involved in NK cell-mediated elimination of HCV-infected hepatocytes. In vitro studies support this by demonstrating that cytokine-activated NK cells can kill HCV-infected hepatocytes via perforin/granzyme34Larkin J. Bost A. Glass J.I. et al.Cytokine-activated natural killer cells exert direct killing of hepatoma cells harboring hepatitis C virus replicons.J Interferon Cytokine Res. 2006; 26: 854-865Google Scholar and TRAIL-mediated mechanisms28Stegmann K.A. Bjorkstrom N.K. Veber H. et al.Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection.Gastroenterology. 2010; 138: 1885-1897Google Scholar and that HCV-infected hepatoma cell lines up-regulate expression of the TRAIL receptors death receptor 4 and death receptor 5.35Zhu H. Dong H. Eksioglu E. et al.Hepatitis C virus triggers apoptosis of a newly developed hepatoma cell line through antiviral defense system.Gastroenterology. 2007; 133: 1649-1659Abstract Full Text Full Text PDF Scopus (87) Google Scholar Further work is needed to dissect the mechanisms underlying NK cells-mediated HCV clearance. Two genetic polymorphisms could have impacted the results of this study: KIR/HLA shown to impact activity of NK cells, and IL28B shown to be the strongest predictor of the outcome of IFN-α therapy (reviewed in Balagopal et al36Balagopal A. Thomas D.L. Thio C.L. IL28B and the control of hepatitis C virus infection.Gastroenterology. 2010; 139: 1865-1876Google Scholar). For example, Knapp et al37Knapp S. Warshow U. Ho K.M. et al.A polymorphism in IL28B distinguishes exposed, uninfected individuals from spontaneous resolvers of HCV infection.Gastroenterology. 2011; 141: 320-325Google Scholar have demonstrated that IL28B and KIR2DL3:HLA-C1 are independently associated with spontaneous resolution of HCV.37Knapp S. Warshow U. Ho K.M. et al.A polymorphism in IL28B distinguishes exposed, uninfected individuals from spontaneous resolvers of HCV infection.Gastroenterology. 2011; 141: 320-325Google Scholar In contrast, Dring et al38Dring M.M. Morrison M.H. McSharry B.P. et al.Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection.Proc Natl Acad Sci U S A. 2011; 108: 5736-5741Google Scholar showed that presence of the nonfavorable KIR allele (KIR2DS3) together with the nonfavorable IL28B (rs12979860) T allele synergized to increase the risk of HCV persistence compared with each factor alone.38Dring M.M. Morrison M.H. McSharry B.P. et al.Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection.Proc Natl Acad Sci U S A. 2011; 108: 5736-5741Google Scholar A recent report by Suppiah et al39Suppiah V, Gaudieri S, Armstrong N, et al. IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis c virus infection in a European cohort: a cross-sectional study. PLoS Med 8(9):e1001092. doi:10.1371/journal.pmed.1001092.Google Scholar has demonstrated that IL28B, HLA-C, and KIR variants additively and interactively predict response to therapy in chronic HCV infection.39Suppiah V, Gaudieri S, Armstrong N, et al. IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis c virus infection in a European cohort: a cross-sectional study. PLoS Med 8(9):e1001092. doi:10.1371/journal.pmed.1001092.Google Scholar In the current study by Ahlenstiel et al, the correlation between NK cell activity and KIR/HLA expression could not be examined owing to limited sample size, although analysis of IL28B polymorphism using the rs12979860 SNP in 26 patients confirmed the expected over-representation of the favorable CC allele in EVR+ patients. The difference in NK cell activation between responders and nonresponders held true even when the analysis was restricted to patients with the favorable CC allele, suggesting that early NK activation during IFN-α therapy are independent of IL28B polymorphism. However, future studies with defined cohorts and larger sample size are needed to better elucidate the interaction between these 2 loci. Little is known about the functional consequences of polymorphism in the IL28B gene region in host immune response. IL28B is a member of the IFN-λ family of type III cytokines that include the closely related and highly homologous IL28A (IFNλ2), IL28B (IFNλ3), and IL-29 (IFNλ1) cytokines with antiviral and immune modulatory effects (reviewed in Balagopal et al36Balagopal A. Thomas D.L. Thio C.L. IL28B and the control of hepatitis C virus infection.Gastroenterology. 2010; 139: 1865-1876Google Scholar). Given the aforementioned immunogenetic associations in HCV infection, it is possible that members of the IFN-λ family can modulate NK activity and that IL28B polymorphism is a marker for this interaction. In fact, IFN-λs were shown to activate NK cells and enhance their capacity to eliminate tumors.40Sato A. Ohtsuki M. Hata M. et al.Antitumor activity of IFN-lambda in murine tumor models.J Immunol. 2006; 176: 7686-7694Google Scholar, 41Wongthida P. Diaz R.M. Galivo F. et al.Type III IFN interleukin-28 mediates the antitumor efficacy of oncolytic virus VSV in immune-competent mouse models of cancer.Cancer Res. 2010; 70: 4539-4549Google Scholar However, Ahlenstiel et al did not find a correlation between NK cell activation and the IL28B genotype in their cohort. Notably, NK cells were shown to express a unique splice variant of the specific IFN-λ or IL28 receptor (IFNλR1 or IL28R1) and exhibit diminished STAT-3 phosphorylation upon stimulation with IFNλ1 and IFNλ2.42Witte K. Gruetz G. Volk H.D. et al.Despite IFN-lambda receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines.Genes Immun. 2009; 10: 702-714Google Scholar IFNλ2 (with 94% homology to IFNλ3 or IL28B) can also inhibit IFN-γ production by NK cells, although this effect was donor dependent and did not correlate with the IL28B genotype.38Dring M.M. Morrison M.H. McSharry B.P. et al.Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection.Proc Natl Acad Sci U S A. 2011; 108: 5736-5741Google Scholar Thus, there are emerging and conflicting studies examining various aspects of IFN-λ, its effect on NK cells, and IL28B polymorphism. We are only starting to unravel the role of NK cells in HCV infection. Based on the current state of knowledge, we can propose a model of NK cell activation during acute HCV and IFN therapy. During acute infection (Figure 1A), NK cells are activated irrespective of the outcome. Several host factors may modulate this activation, including polymorphism in the KIR/HLA loci and IL28B. For example, as plasmacytoid DCs secrete IFN-α upon sensing HCV-infected hepatocytes,43Takahashi K. Asabe S. Wieland S. et al.Plasmacytoid dendritic cells sense hepatitis C virus-infected cells, produce interferon, and inhibit infection.Proc Natl Acad Sci U S A. 2010; 107: 7431-7436Google Scholar NK cells become activated and polarized toward cytotoxicity, thereby promoting enhanced elimination of infected hepatocytes and transfer of HCV antigens to the draining lymph nodes where HCV-specific T cells are primed before they home to the liver to mediate viral clearance. With persistent HCV infection (Figure 1B), activated NK cells may contribute to liver damage or produce regulatory cytokines such as IL-10 and TGF-β, which dampen liver inflammation, as well as adaptive immune responses. Upon initiation of IFN therapy, NK cells are further activated and may participate in both the first- and second-phase decline of viral load via direct cytotoxicity and TRAIL-mediated killing of infected hepatocytes, as suggested by Ahlenstiel et al26Ahlenstiel G. Edlich B. Hogdal L.J. et al.Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C.Gastroenterology. 2011; 141: 1231-1239Google Scholar and others.28Stegmann K.A. Bjorkstrom N.K. Veber H. et al.Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection.Gastroenterology. 2010; 138: 1885-1897Google Scholar, 29Yamagiwa S. Matsuda Y. Ichida T. et al.Sustained response to interferon-alpha plus ribavirin therapy for chronic hepatitis C is closely associated with increased dynamism of intrahepatic natural killer and natural killer T cells.Hepatol Res. 2008; 38: 664-672Google Scholar It is tempting to speculate on a potential role for immunogenetic associations on NK cell function during HCV infection and therapy. In summary, NK cells are the major lymphocytic population in the liver. As discussed, they are activated during acute HCV infection and remain activated during chronic HCV with an aberrant phenotype that is more directly cytolytic, but also regulatory in cytokine profile. The factors that regulate the balance between activation and regulation of NK cells in HCV infection and therapy remain elusive. Emerging studies of NK cells provide new insights to the role of innate and adaptive immune components in HCV infection and therapy. The role of host genetics such as KIR/HLA and IL28B polymorphisms in host immune regulation is another key issue that requires concerted efforts from several groups and large cohorts to better define the underlying pathogenetic mechanisms and develop improved approach to HCV therapy. Early Changes in Natural Killer Cell Function Indicate Virologic Response to Interferon Therapy for Hepatitis CGastroenterologyVol. 141Issue 4PreviewMathematical modeling of hepatitis C virus (HCV) kinetics indicated that cellular immune responses contribute to interferon (IFN)-induced clearance of HCV. We investigated a potential role of natural killer (NK) cells in this process. Full-Text PDF