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Review the Role of Natural Killer Cells in Hepatitis C Infection

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Review the Role of Natural Killer Cells in Hepatitis C Infection Antiviral Therapy 2013; 18:853–865 (doi: 10.3851/IMP2565) Review The role of natural killer cells in hepatitis C infection Jessica Howell1,2,3*, Kumar Visvanathan3 1Liver Transplant Unit, Austin Hospital, Melbourne, Australia 2Department of Medicine, University of Melbourne, Melbourne, Australia 3Innate Immune Laboratory, Monash University, Melbourne, Australia *Corresponding author e-mail: [email protected] HCV infection is an exponentially growing health burden viral infection. A recent explosion in studies exploring the worldwide, with an estimated 170 million people infected. role of NK cells in HCV infection has yielded important Although therapies for HCV are continually improving, mechanistic information and intriguing potential thera- there remain a considerable proportion of patients who peutic options for HCV infection. This review provides a do not achieve viral eradication and develop liver disease. general overview of normal NK cell function and outlines Natural killer (NK) cells are crucial for T-cell activation some of the important mechanisms characterizing the and are one of the first-line sentinel cell responders to immune interplay between NK cells and HCV infection. Introduction The global impact of HCV infection is rapidly grow- cells in HCV infection has yielded important mecha- ing, with an estimated 170 million people infected [1]. nistic information and intriguing potential therapeu- By 2020, it is predicted that the number of chronically tic options for HCV infection. This review provides a infected individuals who go on to develop cirrhosis general overview of normal NK cell function and their will increase by 30% and the number who develop specific role in HCV infection. hepatocellular carcinoma will increase by 80% [2,3]. These sobering figures occur in the context of improv- Natural killer cells ing HCV treatments; nevertheless, there are still a con- siderable number of patients who fail to achieve viral NK cells are mononuclear cells that are primary eradication due to either non-response to treatment or responders to microbial infections and tumour cells, failed tolerance of treatment. but also have an important role in hypersensitivity Most research to date regarding HCV immunity reactions, autoimmunity and allogeneic transplanta- has focused on the role of adaptive immunity in tion [4–6]. Their key functions are initiation of antiviral HCV infection. The role of the innate immune sys- pathways and inflammatory cytokine production, and tem has more recently gained interest for two rea- cytolysis of abnormal target cells [7–9]. Importantly, sons: due to its importance in initial viral recognition NK cells do not require priming to recognize infected after inoculation and due to the fact that adaptive cells and thus form part of the innate immune response, immune responses are not able to completely account but their functions are augmented through activation for the observed immune response to HCV. Innate by other cell types [10]. In this way NK cells are key ini- immune responses help initiate subsequent antibody- tiators of the earliest innate antiviral immune responses. mediated specific adaptive immune responses, which NK cells are CD56-positive, CD3-negative and CD16- are impaired in chronic HCV infection, suggesting a positive cells and comprise approximately 5–20% of potential role for innate immunity in impaired adap- peripheral lymphocytes, but up to 30–50% of intra- tive immune responses to HCV. Natural killer (NK) hepatic lymphocytes [11]. NK cells are controlled by cells contribute to T-cell activation and are one of the surface receptors that engage their appropriate ligand first-line sentinel cell responders to viral infection. A on target cells and this initiates a functional response. recent explosion in studies exploring the role of NK These receptors include killer cell immunoglobulin-like ©2013 International Medical Press 1359-6535 (print) 2040-2058 (online) 853 J Howell & K Visvanathan receptors (KIRs), lectin-like receptors (including hyporesponsive, with impaired cytotoxicity, lower NKG2A-F) and natural cytotoxicity receptors (NKp30, inflammatory cytokine production and greater lev- NKp44 and NKp46) [12]. Most KIRs and CD94/ els of immunoregulatory cytokines, such as IL-10 NKG2A are inhibitory to NK cells [13], whereas secreted [22]. However, this has not yet been con- NKG2D, CD94:NKG2C/E, KIR3DS1 and the natural firmed in human intrahepatic NK cells. cytotoxicity receptors activate NK cells [10]. Other acti- vation markers include CD25, CD69, CD80, CD83 and Hepatic natural killer cells and liver fibrosis CD86, and expression reflects the state of underlying activation and maturity of NK cells [14]. Another specific intrahepatic role for NK cells is inhibi- NK cell populations are heterogenous in their func- tion of fibrogenesis via inhibition of hepatic stellate cells tional responses to stimulation and can be subdivided (HSCs), either directly through induction of HSC apop- based upon their relative expression of CD56 into tosis or indirectly via production of IFN-g, which inhib- CD56bright and -dim subsets, with distinct functional its HSC activation by inducing HSC cell cycle arrest and profiles [15]. However, there is considerable overlap signal transducer and activator of transcription (STAT)1- in function between these different subpopulations as mediated apoptosis [23,24]. Down-regulation or blocking they represent cells at different stages of maturation of KIR leads to enhanced NK-mediated HSC apoptosis rather than distinct cell subtypes. Relatively imma- [23]. NK cells only kill early-activated HSCs, not quiescent ture CD56bright NK cells produce large amounts of or fully activated HSCs, which are distinguished by high cytokine with stimulation, including interleukin (IL)-2, levels of retinoic acid early induced transcript (RAE-1) and IL-12, IL-15 and IL-18, but express low levels of per- TRAIL expression, coupled with down-regulated major forin and are less directly cytotoxic than CD56dim cells. histocompatibility complex class I ligands [24]. Greater They constitute approximately 10% of the peripheral peripheral NK cell cytotoxicity has been associated with blood NK cell population and do not express CD16 or less liver fibrosis in HCV infection and likely reflects this KIR, but do express NKG2A [10]. CD56bright cells do mechanism [25]. however express large amounts of tumour necrosis fac- tor-related apoptosis inducing ligand (TRAIL), which Natural killer cell recruitment and activation binds to death ligands DR4 and DR5 on target cells to induce apoptosis [16]. Importantly, CD56bright cells The key initial step in NK cell activation is recruitment to can mature into CD56dim cells [17]. areas of inflammation. NK cells express several chemokine CD56dim cells, by contrast, constitute approximately receptors in order to be attracted to areas of tissue dam- 90% of peripheral circulating NK cells [10]. CD56dim age [26]. Initial recognition between a target cell and NK cells do not produce as much cytokine as CD56bright cell occurs via activating receptors such as CD16, 2B4, cells in response to target cell engagement, but do pro- NKG2D, DNAX accessory molecule 1 and lymphocyte duce significant amounts of antiviral interferon (IFN)-g function associated antigen-1 (LFA-1) that bind to their and have high levels of perforin expression for cytotoxic- respective ligand expressed on target cells and initiate an ity, particularly when they are of the transient CD56dim inside-out signal for activation of LFA-1 and subsequent CD62L-positive CD57-negative subtype [18]. Termi- adhesion [27]. Target cell recognition by NK cells induces nally differentiated CD56dim cells express high levels of pro-inflammatory chemokine and cytokine release early perforin and also produce greater amounts of cytokine after engagement, including macrophage inhibitory pro- than more immature CD56dim cells in response to tar- tein (MIP)-1a, MIP-1b and RANTES (otherwise known get cell recognition [19]. as CCL5), cytokines tumour necrosis factor (TNF)-a and IFN-g [28]. These cytokines and chemokines then recruit Hepatic natural killer cells additional NK cells and other inflammatory cells to the site of inflammation. Inside-out signalling via LFA-1 The liver contains plentiful amounts of NK cells and requires a low threshold for activation, with increasing many more reside here than are circulating periph- strength of activating stimulus required for MIP-1b secre- erally [20]. The intrahepatic NK cell population tion, CD107a surface expression with degranulation, and dwells within the lumen of the sinusoids [21]. An TNF-a and IFN-g secretion, respectively [15]. This likely important concept in liver immunity is that there is explains why viruses such as HCV can affect some NK a tolerant immune environment to minimize the con- cell functions whilst others remain preserved. stant stimulation from bombardment with antigenic stimuli from the portal system draining the gastroin- Accessory cell stimulation of natural killer cells testinal tract [10]. This has implications for immune responses against intrahepatic viruses, such as HCV. NK cells are activated by cytokines released by neigh- Murine intrahepatic NK cells have been shown to be bouring cells, particularly IL-12 and IL-15 [29]. Myeloid 854 ©2013 International Medical Press Role of natural killer cells in HCV infection dendritic cells (mDCs) produce IL-12 in response to viral the adaptive immune response [44]. NK cell cytokine stimulation
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