Abstract
Viruses, including hepatitis B virus (HBV), are the most prevalent and infectious agents that lead to liver disease in humans. Hepatocellular carcinoma (HCC) and cirrhosis of the liver are the most serious complications arising from prolonged forms of hepatitis B. Previous studies demonstrated that patients suffering from long-term HBV infections are unable to eradicate HBV from hepatocytes completely. The mechanisms responsible for progression of these forms of infection have not yet been clarified. However, it seems that there are differences in genetic and immunological parameters when comparing patients to subjects who successfully clear HBV infections, and these may represent the causes of long-term infection. Natural killer (NK) cells, the main innate immune cells that target viral infections, play important roles in the eradication of HBV from hepatocytes. NK cells carry several stimulatory and inhibitor receptors, and binding of receptors with their ligands results in activation and suppression of NK cells, respectively. The aim of this review is to address the recent information regarding NK cell phenotype, functions and modifications in hepatitis B. This review addresses the recent data regarding the roles of NK cells as novel targets for immunotherapies that target hepatitis B infection. It also discusses the potential to reduce the risk of HCC or cirrhosis of the liver by targeting NK cells.
Similar content being viewed by others
References
Afonina IS, Cullen SP, Martin SJ (2010) Cytotoxic and non-cytotoxic roles of the CTL/NK protease granzyme B. Immunol Rev 235:105–116
Ahmadabadi BN, Hassanshahi G, Arababadi MK, Leanza C, Kennedy D (2012) The IL-10 promoter polymorphism at position -592 is correlated with susceptibility to occult HBV infection. Inflammation 35(3):818–821. doi:10.1007/s10753-011-9381-x
Ahmadabadi BN, Hassanshahi G, Khoramdelazad H, Mirzaei V, Sajadi SM, Hajghani M, Khodadadi H, Pourali R, Arababadi MK, Kennedy D (2013) Downregulation of CCR5 expression on the peripheral blood CD8+ T cells of southeastern Iranian patients with chronic hepatitis B infection. Inflammation 36:136–140
Alison MR, Nicholson LJ, Lin WR (2011) Chronic inflammation and hepatocellular carcinoma. Recent Results Cancer Res 185:135–148
Andrews DM, Andoniou CE, Scalzo AA, van Dommelen SL, Wallace ME, Smyth MJ, Degli-Esposti MA (2005) Cross-talk between dendritic cells and natural killer cells in viral infection. Mol Immunol 42:547–555
Arababadi MK, Pourfathollah AA, Jafarzadeh A, Hassanshahi G (2010) Decreased expression of CCR5 on the NK cells in occult HBV infected patients. Lab Med 41:735–738
Arababadi MK, Pourfathollah AA, Jafarzadeh A, Hassanshahi G, Miohit M, Hajghani M, Ahmadabadi BN, Kennedy D (2010) Evaluation of CCR5 expression on NK cells in Iranian patients with occult hepatitis B infection. Lab Med 41:735–738
Arababadi MK, Pourfathollah AA, Jafarzadeh AA, Hassanshahi G (2010) Serum levels of Interleukin (IL)-10 and IL-17A in occult HBV infected south-east Iranian patients. Hepat Mon 10:31–35
Arababadi MK, Pourfathollah AA, Jafarzadeh A, Hassanshahi G, Daneshmandi S, Shamsizadeh A, Kennedy D (2011) Non-association of IL-12 +1188 and IFN-gamma +874 polymorphisms with cytokines serum level in occult HBV infected patients. Saudi J Gastroenterol 17:30–35
Arababadi MK, Ahmadabadi BN, Kennedy D (2012) Current information on the immunological status of occult hepatitis B infection. Transfusion 52:1819–1826
Attallah AM, Tabll AA, El-Sadany M, Ibrahim TA, El-Dosoky I (2003) Dysregulation of blood lymphocyte subsets and natural killer cells in schistosomal liver cirrhosis and hepatocellular carcinoma. Clin Exp Med 3:181–185
Barreira da Silva R, Munz C (2011) Natural killer cell activation by dendritic cells: balancing inhibitory and activating signals. Cell Mol Life Sci 68:3505–3518
Benson DM, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK (2010) The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116:2286–2294
Bernardini G, Gismondi A, Santoni A (2012) Chemokines and NK cells: regulators of development, trafficking and functions. Immunol Lett 145:39–46
Biber JL, Jabbour S, Parihar R, Dierksheide J, Hu Y, Baumann H, Bouchard P, Caligiuri MA, Carson W (2002) Administration of two macrophage-derived interferon-gamma-inducing factors (IL-12 and IL-15) induces a lethal systemic inflammatory response in mice that is dependent on natural killer cells but does not require interferon-gamma. Cell Immunol 216:31–42
Bocko D, Kosmaczewska A, Ciszak L, Teodorowska R, Frydecka I (2002) CD28 costimulatory molecule—expression, structure and function. Arch Immunol Ther Exp (Warsz) 50:169–177
Böhm W, Schirmbeck R, Elbe A, Melber K, Diminky D, Kraal G, van Rooijen N, Barenholz Y, Reimann J (1995) Exogenous hepatitis B surface antigen particles processed by dendritic cells or macrophages prime murine MHC class I-restricted cytotoxic T lymphocytes in vivo. J Immunol 155:3313–3321
Bonorino P, Ramzan M, Camous X, Dufeu-Duchesne T, Thelu MA, Sturm N, Dariz A, Guillermet C, Pernollet M, Zarski JP, Marche PN, Leroy V, Jouvin-Marche E (2009) Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C. J Hepatol 51:458–467
Braunschweig A, Poehlmann TG, Busch S, Schleussner E, Markert UR (2011) Signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling (SOCS3) balance controls cytotoxicity and IL-10 expression in decidual-like natural killer cell line NK-92. Am J Reprod Immunol 66:329–335
Bryceson YT, Chiang SC, Darmanin S, Fauriat C, Schlums H, Theorell J, Wood SM (2011) Molecular mechanisms of natural killer cell activation. J Innate Immun 3:216–226
Caligiuri MA (2008) Human natural killer cells. Blood 112:461–469
Cao D, Xu H, Guo G, Ruan Z, Fei L, Xie Z, Wu Y, Chen Y (2013) Intrahepatic expression of programmed death-1 and its ligands in patients with HBV-related acute-on-chronic liver failure. Inflammation 36(1):110–120
Carreno V, Zeuzem S, Hopf U, Marcellin P, Cooksley WG, Fevery J, Diago M, Reddy R, Peters M, Rittweger K, Rakhit A, Pardo M (2000) A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B. J Hepatol 32:317–324
Chen Y, Cheng M, Tian Z (2006) Hepatitis B virus down-regulates expressions of MHC class I molecules on hepatoplastoma cell line. Cell Mol Immunol 3:373–378
Cheng Q, Li N, Chen M, Zheng J, Qian Z, Wang X, Huang C, Li Q, Lin Q, Shi G (2013) Fuzheng Huayu inhibits carbon tetrachloride-induced liver fibrosis in mice through activating hepatic NK cells. J Ethnopharmacol 145:175–181
Chisari FV, Isogawa M, Wieland SF (2010) Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris) 58:258–266
Cobleigh MA, Robek MD (2013) Protective and pathological properties of IL-22 in liver disease: implications for viral hepatitis. Am J Pathol 182:21–28
de la Fuente RA, Gutierrez ML, Garcia-Samaniego J, Fernandez-Rodriguez C, Lledo JL, Castellano G (2011) Pathogenesis of occult chronic hepatitis B virus infection. World J Gastroenterol 17:1543–1548
Farag SS, VanDeusen JB, Fehniger TA, Caligiuri MA (2003) Biology and clinical impact of human natural killer cells. Int J Hematol 78:7–17
Gao B, Radaeva S, Jeong WI (2007) Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis. Expert Rev Gastroenterol Hepatol 1:173–180
Garstka MA, Neefjes J (2013) How to target MHC class II into the MIIC compartment. Mol Immunol 55:162–165
Glassner A, Eisenhardt M, Kramer B, Korner C, Coenen M, Sauerbruch T, Spengler U, Nattermann J (2012) NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab Invest 92:967–977
Gunturi A, Berg RE, Forman J (2004) The role of CD94/NKG2 in innate and adaptive immunity. Immunol Res 30:29–34
Hellerbrand C (2013) Hepatic stellate cells-the pericytes in the liver. Pflugers Arch 465(6):775–778
Hulikova K, Benson V, Svoboda J, Sima P, Fiserova A (2009) N-Acetyl-d-glucosamine-coated polyamidoamine dendrimer modulates antibody formation via natural killer cell activation. Int Immunopharmacol 9:792–799
Inngjerdingen M, Kveberg L, Naper C, Vaage JT (2011) Natural killer cell subsets in man and rodents. Tissue Antigens 78:81–88
Ishimaru H, Matsuda T, Hara T (1989) Circulating mature NK (Leu11+) cells positive for IL2 receptor and HLA-DR in patients with various liver diseases and asymptomatic HBsAg carriers. Nihon Shokakibyo Gakkai Zasshi 86:2721–2727
Jinushi M, Takehara T, Tatsumi T, Yamaguchi S, Sakamori R, Hiramatsu N, Kanto T, Ohkawa K, Hayashi N (2007) Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4+ CD25+ T cells with PD-1-dependent regulatory activities. Immunology 120:73–82
Jobim M, Jobim LF (2008) Natural killer cells and immune surveillance. J Pediatr (Rio J) 84:S58–S67
Ju Y, Hou N, Meng J, Wang X, Zhang X, Zhao D, Liu Y, Zhu F, Zhang L, Sun W, Liang X, Gao L, Ma C (2010) T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol 52:322–329
Kakimi K, Guidotti LG, Koezuka Y, Chisari FV (2000) Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 192:921–930
Kanchan V, Panda AK (2007) Interactions of antigen-loaded polylactide particles with macrophages and their correlation with the immune response. Biomaterials 28:5344–5357
Kennedy M, Alexopoulos SP (2010) Hepatitis B virus infection and liver transplantation. Curr Opin Organ Transplant 15:310–315
Khorramdelazad H, Hassanshahi G, Ahmadabadi BN, Arababadi MK (2012) High serum levels of TGF-β in Iranians with chronic HBV infection. Hepat Mon 12:e7581
Krzewski K, Coligan JE (2012) Human NK cell lytic granules and regulation of their exocytosis. Front Immunol 3:335
Lee CS, Lee FZ (1989) Natural killer cell activity in hepatocellular carcinoma patients. Taiwan Yi Xue Hui Za Zhi 88:478–482
Lee CS (1991) Lymphocytes and their subsets in the peripheral blood of hepatocellular carcinoma patients. J Formos Med Assoc 90:626–630
Lee J, Chae D, Kim S, Nam E, Jang M, Lee J, Kim H, Yoo J (2004) Expression of FasL and perforin/granzyme B mRNA in chronic hepatitis B virus infection. J Viral Hepat 11:130–135
Li F, Wei H, Gao Y, Xu L, Yin W, Sun R, Tian Z (2013) Blocking the natural killer (NK) cell inhibitory receptor NKG2A increases activity of human NK cells and clears HBV infection in mice. Gastroenterology 144(2):392–401
Li J, Han Y, Jin K, Wan Y, Wang S, Liu B, Liu Y, Lu S, Huang Z (2011) Dynamic changes of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and natural killer T (NKT) cells in patients with acute hepatitis B infection. Virol J 8:199
Li M, Yao Y, Gao YQ (2010) Expression profile of immune effector molecules in natural killer cells in patients with chronic hepatitis B. Zhonghua Gan Zang Bing Za Zhi 18:96–100
Lu Z, Zhang B, Chen S, Gai Z, Feng Z, Liu X, Liu Y, Wen X, Li L, Jiao Y, Ma C, Shao S, Cui X, Chen G, Li J, Zhao Y (2008) Association of KIR genotypes and haplotypes with susceptibility to chronic hepatitis B virus infection in Chinese Han population. Cell Mol Immunol 5:457–463
Ma J, Guo X, Wu X, Li J, Zhu X, Li Z, Pan L, Li T, Li H, Liu Y (2010) Association of NKG2D genetic polymorphism with susceptibility to chronic hepatitis B in a Han Chinese population. J Med Virol 82:1501–1507
Martin-Fontecha A, Lord GM, Brady HJ (2011) Transcriptional control of natural killer cell differentiation and function. Cell Mol Life Sci 68:3495–3503
Martinet J, Dufeu-Duchesne T, Bruder Costa J, Larrat S, Marlu A, Leroy V, Plumas J, Aspord C (2012) Altered functions of plasmacytoid dendritic cells and reduced cytolytic activity of natural killer cells in patients with chronic HBV infection. Gastroenterology 143(6):1586–1596
Mohammadi Nejad M, Salehi E, Mesdaghi M, Atarod L, Movahedi M, Gheflati Z, Aboufazeli T, Vodjgani M (2013) Increased expression of CD69 antigen on human peripheral blood natural killer cells in patients with allergic rhinitis. Iran J Allergy Asthma Immunol 12:68–74
Nakamura T, Morizane T, Watanabe T, Tsuchimoto K, Inagaki Y, Kumagai N, Tsuchiya M (1983) Decreased natural killer activity in patients with liver cirrhosis. Int J Cancer 32:573–575
Okazaki A, Hiraga N, Imamura M, Hayes CN, Tsuge M, Takahashi S, Aikata H, Abe H, Miki D, Ochi H, Tateno C, Yoshizato K, Ohdan H, Chayama K (2012) Severe necroinflammatory reaction caused by natural killer cell-mediated Fas/Fas ligand interaction and dendritic cells in human hepatocyte chimeric mouse. Hepatology 56:555–566
Oliviero B, Varchetta S, Paudice E, Michelone G, Zaramella M, Mavilio D, De Filippi F, Bruno S, Mondelli MU (2009) Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 137:1151–1160 (pp 1160 e1151–1157)
Papatheodoridis GV (2013) Why do I treat HBeAg-negative chronic hepatitis B patients with nucleos(t)ide analogues? Liver Int 33(Suppl 1):151–156
Park GH, Kim KY, Cheong JY, Cho SW, Kwack K (2012) Association of GNLY genetic polymorphisms with chronic liver disease in a Korean population. DNA Cell Biol 31:1492–1498
Peppa D, Micco L, Javaid A, Kennedy PT, Schurich A, Dunn C, Pallant C, Ellis G, Khanna P, Dusheiko G, Gilson RJ, Maini MK (2010) Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog 6:e1001227
Pinzani M, Macias-Barragan J (2010) Update on the pathophysiology of liver fibrosis. Expert Rev Gastroenterol Hepatol 4:459–472
Poggi A, Prevosto C, Zancolli M, Canevali P, Musso A, Zocchi MR (2007) NKG2D and natural cytotoxicity receptors are involved in natural killer cell interaction with self-antigen presenting cells and stromal cells. Ann N Y Acad Sci 1109:47–57
Ratnam DT, Sievert W, Visvanathan K (2012) Natural killer cells display impaired responses to toll like receptor 9 that support viral persistence in chronic hepatitis B. Cell Immunol 279:109–115
Rehermann B (2013) Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med 19:859–868
Rigopoulou EI, Suri D, Chokshi S, Mullerova I, Rice S, Tedder RS, Williams R, Naoumov NV (2005) Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity. Hepatology 42:1028–1036
Romee R, Schneider SE, Leong JW, Chase JM, Keppel CR, Sullivan RP, Cooper MA, Fehniger TA (2012) Cytokine activation induces human memory-like NK cells. Blood 120:4751–4760
Rousalova I, Krepela E (2010) Granzyme B-induced apoptosis in cancer cells and its regulation (review). Int J Oncol 37:1361–1378
Scaglione SJ, Lok AS (2012) Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology 142(1360–1368):e1361
Seijkens T, Engel D, Tjwa M, Lutgens E (2010) The role of CD154 in haematopoietic development. Thromb Haemost 104:693–701
Shi CC, Tjwa ET, Biesta PJ, Boonstra A, Xie Q, Janssen HL, Woltman AM (2012) Hepatitis B virus suppresses the functional interaction between natural killer cells and plasmacytoid dendritic cells. J Viral Hepat 19:e26–e33
Sitia G, Isogawa M, Kakimi K, Wieland SF, Chisari FV, Guidotti LG (2002) Depletion of neutrophils blocks the recruitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus-specific cytotoxic T lymphocytes. Proc Natl Acad Sci 99:13717–13722
Sun C, Fu B, Gao Y, Liao X, Sun R, Tian Z, Wei H (2012) TGF-beta1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence. PLoS Pathog 8:e1002594
Szabo G, Dolganiuc A (2008) The role of plasmacytoid dendritic cell-derived IFN alpha in antiviral immunity. Crit Rev Immunol 28:61–94
Tang H, Li C, Wang L, Zhang H, Fan Z (2012) Granzyme H of cytotoxic lymphocytes is required for clearance of the hepatitis B virus through cleavage of the hepatitis B virus X protein. J Immunol 188:824–831
Tang Q, Ahn YO, Southern P, Blazar BR, Miller JS, Verneris MR (2011) Development of IL-22-producing NK lineage cells from umbilical cord blood hematopoietic stem cells in the absence of secondary lymphoid tissue. Blood 117:4052–4055
Tang ST, Wang M, Lamberth K, Harndahl M, Dziegiel M, Claesson M, Buus S, Lund O (2008) MHC-I-restricted epitopes conserved among variola and other related orthopoxviruses are recognized by T cells 30 years after vaccination. Arch Virol 153:1833–1844
Tefanova VT, Priimiagi LS, Tallo TG (2001) Functional and metabolic activity of peripheral blood neutrophils in acute viral hepatitis B and C. Zh Mikrobiol Epidemiol Immunobiol 43–47
Terrazzano G, Pisanti S, Grimaldi S, Sica M, Fontana S, Carbone E, Zappacosta S, Ruggiero G (2004) Interaction between natural killer and dendritic cells: the role of CD40, CD80 and major histocompatibility complex class i molecules in cytotoxicity induction and interferon-gamma production. Scand J Immunol 59(4):356–362
Tjwa ET, van Oord GW, Hegmans JP, Janssen HL, Woltman AM (2011) Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol 54:209–218
Tjwa ET, van Oord GW, Biesta PJ, Boonstra A, Janssen HL, Woltman AM (2012) Restoration of TLR3-activated myeloid dendritic cell activity leads to improved natural killer cell function in chronic hepatitis B virus infection. J Virol 86:4102–4109
Tujios SR, Lee WM (2013) Update in the management of chronic hepatitis B. Curr Opin Gastroenterol 29:250–256
Vargas CL, Poursine-Laurent J, Yang L, Yokoyama WM (2011) Development of thymic NK cells from double negative 1 thymocyte precursors. Blood 118:3570–3578
Vincent IE, Zannetti C, Lucifora J, Norder H, Protzer U, Hainaut P, Zoulim F, Tommasino M, Trepo C, Hasan U, Chemin I (2011) Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells. PLoS One 6:e26315
Wang S, Xia P, Shi L, Fan Z (2012) FADD cleavage by NK cell granzyme M enhances its self-association to facilitate procaspase-8 recruitment for auto-processing leading to caspase cascade. Cell Death Differ 19:605–615
Wiesmayr S, Webber SA, Macedo C, Popescu I, Smith L, Luce J, Metes D (2012) Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD. Eur J Immunol 42:541–550
Xibing G, Xiaojuan Y, Juanhua W, Zhong H (2013) Relationship between HBV genotypes B, C and follicular helper T cells in patients with chronic hepatitis B and its significance. Hepat Mon 13:e6221
Yamagiwa S, Kamimura H, Ichida T (2009) Natural killer cell receptors and their ligands in liver diseases. Med Mol Morphol 42:1–8
Yin W, Xu L, Sun R, Wei H, Tian Z (2012) Interleukin-15 suppresses hepatitis B virus replication via IFN-beta production in a C57BL/6 mouse model. Liver Int 32:1306–1314
Yoshida O, Akbar F, Miyake T, Abe M, Matsuura B, Hiasa Y, Onji M (2008) Impaired dendritic cell functions because of depletion of natural killer cells disrupt antigen-specific immune responses in mice: restoration of adaptive immunity in natural killer-depleted mice by antigen-pulsed dendritic cell. Clin Exp Immunol 152:174–181
Zeng XH, Sha WH, Li YY, Nie YQ, Li QN, Liang PZ (2009) Expression of NK cells receptor NKG2D from peripheral blood in patients with primary hepatic carcinoma and its clinical significance. Zhonghua Yi Xue Za Zhi 89:1272–1274
Zhang C, Wang Y, Zhou Z, Zhang J, Tian Z (2009) Sodium butyrate upregulates expression of NKG2D ligand MICA/B in HeLa and HepG2 cell lines and increases their susceptibility to NK lysis. Cancer Immunol Immunother 58:1275–1285
Zhao J, Li Y, Jin L, Zhang S, Fan R, Sun Y, Zhou C, Shang Q, Li W, Zhang Z, Wang FS (2012) Natural killer cells are characterized by the concomitantly increased interferon-gamma and cytotoxicity in acute resolved hepatitis B patients. PLoS One 7:e49135
Zhi-ming L, Yu-lian J, Zhao-lei F, Chun-xiao W, Zhen-fang D, Bing-chang Z, Yue-ran Z (2007) Polymorphisms of killer cell immunoglobulin-like receptor gene: possible association with susceptibility to or clearance of hepatitis B virus infection in Chinese Han population. Croat Med J 48:800–806
Zhu J, Huang X, Yang Y (2010) NKG2D is required for NK cell activation and function in response to E1-deleted adenovirus. J Immunol 185:7480–7486
Zhu R, Mancini-Bourgine M, Zhang XM, Bayard F, Deng Q, Michel ML (2011) Plasmid vector-linked maturation of natural killer (NK) cells is coupled to antigen-dependent NK cell activation during DNA-based immunization in mice. J Virol 85:10201–10212
Acknowledgments
This project was supported by a grant from the Rafsanjan University of Medical Sciences.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shabani, Z., Bagheri, M., Zare-Bidaki, M. et al. NK cells in hepatitis B virus infection: a potent target for immunotherapy. Arch Virol 159, 1555–1565 (2014). https://doi.org/10.1007/s00705-013-1965-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00705-013-1965-3