logo

SCIENCE CHINA Life Sciences, Volume 61, Issue 12: 1477-1485(2018) https://doi.org/10.1007/s11427-018-9407-2

NK cells in liver homeostasis and viral hepatitis

Hui Peng1,2,*, Zhigang Tian1,2,*
More info
  • ReceivedJul 17, 2018
  • AcceptedAug 15, 2018
  • PublishedNov 2, 2018

Abstract

As an important member of the innate immune system, natural killer (NK) cells are well known for their rapid and efficient immune responses against infectious agents and tumors. NK cells are widely distributed throughout the body and are particularly enriched within the liver, where they display unique phenotypic and functional properties, playing important roles in various liver diseases. Herein, we present an overview of liver NK cell properties with regard to phenotype, function, and subset composition at steady state, and we also summarize the complex reciprocal interactions between liver NK cells and other cell types within the local environment of the liver. We also provide an overview of recent advances demonstrating the roles of NK cells in viral hepatitis, including a discussion of NK cell altered states and their beneficial versus harmful effects during hepatitis B virus and hepatitis C virus infection.


Funded by

the National Natural Science Foundation of China(81788101,81761128013,31390433,81571522,91642105,91542114,91542000)

Chinese Academy of Sciences(XDPB030301)


Acknowledgment

This work was supported by the National Natural Science Foundation of China (81788101, 81761128013, 31390433, 81571522, 91642105, 91542114, 91542000) and Chinese Academy of Sciences (XDPB030301).


Interest statement

The author(s) declare that they have no conflict of interest.


References

[1] Ahlenstiel G., Edlich B., Hogdal L.J., Rotman Y., Noureddin M., Feld J.J., Holz L.E., Titerence R.H., Liang T.J., Rehermann B.. Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C. Gastroenterology, 2011, 141: 1231-1239.e2 CrossRef PubMed Google Scholar

[2] Ahlenstiel, G., Martin, M.P., Gao, X., Carrington, M., and Rehermann, B. (2008). Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses. J Clin Invest 118, 1017‒1026. Google Scholar

[3] Ahlenstiel G., Titerence R.H., Koh C., Edlich B., Feld J.J., Rotman Y., Ghany M.G., Hoofnagle J.H., Liang T.J., Heller T., et al. Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner. Gastroenterology, 2010, 138: 325-335.e2 CrossRef PubMed Google Scholar

[4] Amadei B., Urbani S., Cazaly A., Fisicaro P., Zerbini A., Ahmed P., Missale G., Ferrari C., Khakoo S.I.. Activation of natural killer cells during acute infection with hepatitis C virus. Gastroenterology, 2010, 138: 1536-1545 CrossRef PubMed Google Scholar

[5] Andreotti J.P., Paiva A.E., Prazeres P.H.D.M., Guerra D.A.P., Silva W.N., Vaz R.S., Mintz A., Birbrair A.. The role of natural killer cells in the uterine microenvironment during pregnancy. Cell Mol Immunol, 2018, 15: 941-943 CrossRef PubMed Google Scholar

[6] Aw Yeang H.X., Piersma S.J., Lin Y., Yang L., Malkova O.N., Miner C., Krupnick A.S., Chapman W.C., Yokoyama W.M.. Cutting edge: human CD49e NK cells are tissue resident in the liver. J Immunol, 2017, 198: 1417-1422 CrossRef PubMed Google Scholar

[7] Beraza N., Malato Y., Sander L.E., Al-Masaoudi M., Freimuth J., Riethmacher D., Gores G.J., Roskams T., Liedtke C., Trautwein C.. Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. J Exp Med, 2009, 206: 1727-1737 CrossRef PubMed Google Scholar

[8] Bi J., Zheng X., Chen Y., Wei H., Sun R., Tian Z.. TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk. Hepatology, 2014, 60: 1389-1398 CrossRef PubMed Google Scholar

[9] Billerbeck E., Wolfisberg R., Fahnøe U., Xiao J.W., Quirk C., Luna J.M., Cullen J.M., Hartlage A.S., Chiriboga L., Ghoshal K., et al. Mouse models of acute and chronic hepacivirus infection. Science, 2017, 357: 204-208 CrossRef PubMed ADS Google Scholar

[10] Boltjes A., van Montfoort N., Biesta P.J., Op den Brouw M.L., Kwekkeboom J., van der Laan L.J.W., Janssen H.L.A., Boonstra A., Woltman A.M.. Kupffer cells interact with hepatitis B surface antigen in vivo and in vitro, leading to proinflammatory cytokine production and natural killer cell function. J Infect Dis, 2015, 211: 1268-1278 CrossRef PubMed Google Scholar

[11] Burt B.M., Plitas G., Zhao Z., Bamboat Z.M., Nguyen H.M., Dupont B., DeMatteo R.P.. The lytic potential of human liver NK cells is restricted by their limited expression of inhibitory killer Ig-like receptors. J Immunol, 2009, 183: 1789-1796 CrossRef Google Scholar

[12] Chen Y., Wei H., Sun R., Dong Z., Zhang J., Tian Z.. Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells. Hepatology, 2007, 46: 706-715 CrossRef PubMed Google Scholar

[13] Crouse J., Xu H.C., Lang P.A., Oxenius A.. NK cells regulating T cell responses: mechanisms and outcome. Trends Immunol, 2015, 36: 49-58 CrossRef PubMed Google Scholar

[14] Das A., Ellis G., Pallant C., Lopes A.R., Khanna P., Peppa D., Chen A., Blair P., Dusheiko G., Gill U., et al. IL-10-producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection. J Immunol, 2012, 189: 3925-3935 CrossRef Google Scholar

[15] De Maria A., Fogli M., Mazza S., Basso M., Picciotto A., Costa P., Congia S., Mingari M.C., Moretta L.. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients. Eur J Immunol, 2007, 37: 445-455 CrossRef PubMed Google Scholar

[16] Dong Z., Wei H., Sun R., Hu Z., Gao B., Tian Z.. Involvement of natural killer cells in PolyI:C-induced liver injury. J Hepatology, 2004, 41: 966-973 CrossRef PubMed Google Scholar

[17] Fasbender F., Widera A., Hengstler J.G., Watzl C.. Natural killer cells and liver fibrosis. Front Immunol, 2016, 7: 19 CrossRef PubMed Google Scholar

[18] Fernández-Álvarez S., Gutiérrez-de Juan V., Zubiete-Franco I., Barbier-Torres L., Lahoz A., Parés A., Luka Z., Wagner C., Lu S.C., Mato J.M., et al. TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency. Lab Invest, 2015, 95: 223-236 CrossRef PubMed Google Scholar

[19] Fisicaro P., Valdatta C., Boni C., Massari M., Mori C., Zerbini A., Orlandini A., Sacchelli L., Missale G., Ferrari C.. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut, 2009, 58: 974-982 CrossRef PubMed Google Scholar

[20] Fu B., Zhou Y., Ni X., Tong X., Xu X., Dong Z., Sun R., Tian Z., Wei H.. Natural killer cells promote fetal development through the secretion of growth-promoting factors. Immunity, 2017, 47: 1100-1113.e6 CrossRef PubMed Google Scholar

[21] Gao B.. Basic liver immunology. Cell Mol Immunol, 2016, 13: 265-266 CrossRef PubMed Google Scholar

[22] Gao B., Jeong W.I., Tian Z.. Liver: An organ with predominant innate immunity. Hepatology, 2008, 47: 729-736 CrossRef PubMed Google Scholar

[23] Gao B., Radaeva S.. Natural killer and natural killer T cells in liver fibrosis. BBA‒Mol Basis Dis, 2013, 1832: 1061-1069 CrossRef PubMed Google Scholar

[24] Geddawy A., Ibrahim Y.F., Elbahie N.M., Ibrahim M.A.. Direct acting anti-hepatitis C virus drugs: clinical pharmacology and future direction. J Trans Intern Med, 2017, 5: 8-17 CrossRef PubMed Google Scholar

[25] Guidotti L.G., Rochford R., Chung J., Shapiro M., Purcell R., Chisari F.V.. Viral clearance without destruction of infected cells during acute HBV infection. Science, 1999, 284: 825-829 CrossRef ADS Google Scholar

[26] Gur C., Doron S., Kfir-Erenfeld S., Horwitz E., Abu-Tair L., Safadi R., Mandelboim O.. NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut, 2012, 61: 885-893 CrossRef PubMed Google Scholar

[27] Harmon C., Robinson M.W., Fahey R., Whelan S., Houlihan D.D., Geoghegan J., O’Farrelly C.. Tissue-resident Eomeshi T-betlo CD56bright NK cells with reduced proinflammatory potential are enriched in the adult human liver. Eur J Immunol, 2016, 46: 2111-2120 CrossRef PubMed Google Scholar

[28] Horras C.J., Lamb C.L., Mitchell K.A.. Regulation of hepatocyte fate by interferon-γ. Cytokine Growth Factor Rev, 2011, 22: 35-43 CrossRef PubMed Google Scholar

[29] Horst A.K., Neumann K., Diehl L., Tiegs G.. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol, 2016, 13: 277-292 CrossRef PubMed Google Scholar

[30] Hou X., Zhou R., Wei H., Sun R., Tian Z.. NKG2D-retinoic acid early inducible-1 recognition between natural killer cells and Kupffer cells in a novel murine natural killer cell-dependent fulminant hepatitis. Hepatology, 2009, 49: 940-949 CrossRef PubMed Google Scholar

[31] Huang M., Sun R., Wei H., Tian Z.. Simultaneous knockdown of multiple ligands of innate receptor NKG2D prevents natural killer cell-mediated fulminant hepatitis in mice. Hepatology, 2013, 57: 277-288 CrossRef PubMed Google Scholar

[32] Ishiyama K., Ohdan H., Ohira M., Mitsuta H., Arihiro K., Asahara T.. Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans. Hepatology, 2006, 43: 362-372 CrossRef PubMed Google Scholar

[33] Jeong W.I., Park O., Radaeva S., Gao B.. STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell proliferation and stimulating NK cell cytotoxicity. Hepatology, 2006, 44: 1441-1451 CrossRef PubMed Google Scholar

[34] Kahraman A., Schlattjan M., Kocabayoglu P., Yildiz-Meziletoglu S., Schlensak M., Fingas C.D., Wedemeyer I., Marquitan G., Gieseler R.K., Baba H.A., et al. Major histocompatibility complex class I-related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis. Hepatology, 2010, 51: 92-102 CrossRef PubMed Google Scholar

[35] Khakoo S.I., Thio C.L., Martin M.P., Brooks C.R., Gao X., Astemborski J., Cheng J., Goedert J.J., Vlahov D., Hilgartner M., et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science, 2004, 305: 872-874 CrossRef PubMed ADS Google Scholar

[36] Krizhanovsky V., Yon M., Dickins R.A., Hearn S., Simon J., Miething C., Yee H., Zender L., Lowe S.W.. Senescence of activated stellate cells limits liver fibrosis. Cell, 2008, 134: 657-667 CrossRef PubMed Google Scholar

[37] Lang P.A., Lang K.S., Xu H.C., Grusdat M., Parish I.A., Recher M., Elford A.R., Dhanji S., Shaabani N., Tran C.W., et al. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc Natl Acad Sci USA, 2012, 109: 1210-1215 CrossRef PubMed ADS Google Scholar

[38] Lassen M.G., Lukens J.R., Dolina J.S., Brown M.G., Hahn Y.S.. Intrahepatic IL-10 maintains NKG2A+ Ly49 liver NK cells in a functionally hyporesponsive state. J Immunol, 2010, 184: 2693-2701 CrossRef Google Scholar

[39] Li F., Wei H., Wei H., Gao Y., Xu L., Yin W., Sun R., Tian Z.. Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice. Gastroenterology, 2013, 144: 392-401 CrossRef PubMed Google Scholar

[40] Li H., Zhai N., Wang Z., Song H., Yang Y., Cui A., Li T., Wang G., Niu J., Crispe I.N., et al. Regulatory NK cells mediated between immunosuppressive monocytes and dysfunctional T cells in chronic HBV infection. Gut, 2018, 67: 2035-2044 CrossRef PubMed Google Scholar

[41] Li Y., Cao G., Zheng X., Wang J., Wei H., Tian Z., Sun R.. CRACC-CRACC interaction between Kupffer and NK cells contributes to poly I:C/D-GalN induced hepatitis. PLoS ONE, 2013, 8: e76681 CrossRef PubMed ADS Google Scholar

[42] Li Y., Yin J., Li T., Huang S., Yan H., Leavenworth J.M., Wang X.. NK cell-based cancer immunotherapy: from basic biology to clinical application. Sci China Life Sci, 2015, 58: 1233-1245 CrossRef PubMed Google Scholar

[43] Liang S.. IFNα regulates NK cell cytotoxicity through STAT1 pathway. Cytokine, 2003, 23: 190-199 CrossRef Google Scholar

[44] Liu S., Chen L., Zeng Y., Si L., Guo X., Zhou J., Fang D., Zeng G., Jiang L.. Suppressed expression of miR-378 targeting gzmb in NK cells is required to control dengue virus infection. Cell Mol Immunol, 2016, 13: 700-708 CrossRef PubMed Google Scholar

[45] Liu Y., Zheng J., Liu Y., Wen L., Huang L., Xiang Z., Lam K.T., Lv A., Mao H., Lau Y.L., et al. Uncompromised NK cell activation is essential for virus-specific CTL activity during acute influenza virus infection. Cell Mol Immunol, 2018, 15: 827-837 CrossRef PubMed Google Scholar

[46] Lunemann S., Malone D.F.G., Hengst J., Port K., Grabowski J., Deterding K., Markova A., Bremer B., Schlaphoff V., Cornberg M., et al. Compromised function of natural killer cells in acute and chronic viral hepatitis. J Infect Dis, 2014, 209: 1362-1373 CrossRef PubMed Google Scholar

[47] Maini M.K., Peppa D.. NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol, 2013, 4: 57 CrossRef PubMed Google Scholar

[48] Marquardt N., Béziat V., Nyström S., Hengst J., Ivarsson M.A., Kekäläinen E., Johansson H., Mjösberg J., Westgren M., Lankisch T.O., et al. Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J Immunol, 2015, 194: 2467-2471 CrossRef Google Scholar

[49] Martín-Fontecha A., Thomsen L.L., Brett S., Gerard C., Lipp M., Lanzavecchia A., Sallusto F.. Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming. Nat Immunol, 2004, 5: 1260-1265 CrossRef PubMed Google Scholar

[50] Melhem A., Muhanna N., Bishara A., Alvarez C.E., Ilan Y., Bishara T., Horani A., Nassar M., Friedman S.L., Safadi R.. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatology, 2006, 45: 60-71 CrossRef PubMed Google Scholar

[51] Miyagi T., Gil M.P., Wang X., Louten J., Chu W.M., Biron C.A.. High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells. J Exp Med, 2007, 204: 2383-2396 CrossRef PubMed Google Scholar

[52] Miyagi T., Takehara T., Nishio K., Shimizu S., Kohga K., Li W., Tatsumi T., Hiramatsu N., Kanto T., Hayashi N.. Altered interferon-α-signaling in natural killer cells from patients with chronic hepatitis C virus infection. J Hepatology, 2010, 53: 424-430 CrossRef PubMed Google Scholar

[53] Moroso V., Metselaar H.J., Mancham S., Tilanus H.W., Eissens D., van der Meer A., van der Laan L.J.W., Kuipers E.J., Joosten I., Kwekkeboom J.. Liver grafts contain a unique subset of natural killer cells that are transferred into the recipient after liver transplantation. Liver Transpl, 2010, 16: 895-908 CrossRef PubMed Google Scholar

[54] Ning G., Li Y.T., Chen Y.M., Zhang Y., Zeng Y.F., Lin C.S.. Dynamic changes of the frequency of classic and inflammatory monocytes subsets and natural killer cells in chronic hepatitis C patients treated by direct-acting antiviral agents. Can J Gastroenterol, 2017, 2017: 1-8 CrossRef PubMed Google Scholar

[55] Ochi M., Ohdan H., Mitsuta H., Onoe T., Tokita D., Hara H., Ishiyama K., Zhou W., Tanaka Y., Asahara T.. Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice. Hepatology, 2004, 39: 1321-1331 CrossRef PubMed Google Scholar

[56] Okazaki A., Hiraga N., Imamura M., Hayes C.N., Tsuge M., Takahashi S., Aikata H., Abe H., Miki D., Ochi H., et al. Severe necroinflammatory reaction caused by natural killer cell-mediated Fas/Fas ligand interaction and dendritic cells in human hepatocyte chimeric mouse. Hepatology, 2012, 56: 555-566 CrossRef PubMed Google Scholar

[57] Oliviero B., Varchetta S., Paudice E., Michelone G., Zaramella M., Mavilio D., De Filippi F., Bruno S., Mondelli M.U.. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology, 2009, 137: 1151-1160.e7 CrossRef PubMed Google Scholar

[58] Peng H., Jiang X., Chen Y., Sojka D.K., Wei H., Gao X., Sun R., Yokoyama W.M., Tian Z.. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest, 2013, 123: 1444-1456 CrossRef PubMed Google Scholar

[59] Peng H., Sun R.. . Liver-resident NK cells and their potential functions. Cell Mol Immunol, 2017, 14: 890-894 CrossRef PubMed Google Scholar

[60] Peng H., Tian Z.. Tissue-resident natural killer cells in the livers. Sci China Life Sci, 2016, 59: 1218-1223 CrossRef PubMed Google Scholar

[61] Peng H., Wisse E., Tian Z.. Liver natural killer cells: subsets and roles in liver immunity. Cell Mol Immunol, 2016, 13: 328-336 CrossRef PubMed Google Scholar

[62] Peppa D., Gill U.S., Reynolds G., Easom N.J.W., Pallett L.J., Schurich A., Micco L., Nebbia G., Singh H.D., Adams D.H., et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med, 2013, 210: 99-114 CrossRef PubMed Google Scholar

[63] Peppa D., Micco L., Javaid A., Kennedy P.T.F., Schurich A., Dunn C., Pallant C., Ellis G., Khanna P., Dusheiko G., et al. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog, 2010, 6: e1001227 CrossRef PubMed Google Scholar

[64] Poggi A., Zocchi M.R.. NK cell autoreactivity and autoimmune diseases. Front Immunol, 2014, 5 CrossRef PubMed Google Scholar

[65] Protzer U., Maini M.K., Knolle P.A.. Living in the liver: hepatic infections. Nat Rev Immunol, 2012, 12: 201-213 CrossRef PubMed Google Scholar

[66] Radaeva S., Sun R., Jaruga B., Nguyen V.T., Tian Z., Gao B.. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology, 2006, 130: 435-452 CrossRef PubMed Google Scholar

[67] Raulet D.H., Gasser S., Gowen B.G., Deng W., Jung H.. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol, 2013, 31: 413-441 CrossRef PubMed Google Scholar

[68] Rehermann B.. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med, 2013, 19: 859-868 CrossRef PubMed Google Scholar

[69] Robinson M.W., Harmon C., O’Farrelly C.. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol, 2016, 13: 267-276 CrossRef PubMed Google Scholar

[70] Rockey D.C., Maher J.J., Jarnagin W.R., Gabbiani G., Friedman S.L.. Inhibition of rat hepatic lipocyte activation in culture by interferon-γ. Hepatology, 1992, 16: 776-784 CrossRef Google Scholar

[71] Sato Y., Tsukada K., Matsumot Y., Ab T.. Interferon-γ inhibits liver regeneration by stimulating major histocompatibility complex class II antigen expression by regenerating liver. Hepatology, 1993, 18: 340-346 CrossRef Google Scholar

[72] Saunders P.M., Vivian J.P., O’Connor G.M., Sullivan L.C., Pymm P., Rossjohn J., Brooks A.G.. A bird’s eye view of NK cell receptor interactions with their MHC class I ligands. Immunol Rev, 2015, 267: 148-166 CrossRef PubMed Google Scholar

[73] Serti E., Chepa-Lotrea X., Kim Y.J., Keane M., Fryzek N., Liang T.J., Ghany M., Rehermann B.. Successful interferon-free therapy of chronic hepatitis C virus infection normalizes natural killer cell function. Gastroenterology, 2015, 149: 190-200.e2 CrossRef PubMed Google Scholar

[74] Shin E.C., Sung P.S., Park S.H.. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol, 2016, 16: 509-523 CrossRef PubMed Google Scholar

[75] Simonetta F., Alvarez M., Negrin R.S.. Natural killer cells in graft-versus-host-disease after allogeneic hematopoietic cell transplantation. Front Immunol, 2017, 8: 465 CrossRef PubMed Google Scholar

[76] Sojka D.K., Plougastel-Douglas B., Yang L., Pak-Wittel M.A., Artyomov M.N., Ivanova Y., Zhong C., Chase J.M., Rothman P.B., Yu J., et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. eLife, 2014, 3: e01659 CrossRef Google Scholar

[77] Spaan M., van Oord G., Kreefft K., Hou J., Hansen B.E., Janssen H.L.A., de Knegt R.J., Boonstra A.. Immunological analysis during interferon-free therapy for chronic hepatitis C virus infection reveals modulation of the natural killer cell compartment. J Infect Dis, 2016, 213: 216-223 CrossRef PubMed Google Scholar

[78] Stegmann K.A., Robertson F., Hansi N., Gill U., Pallant C., Christophides T., Pallett L.J., Peppa D., Dunn C., Fusai G., et al. CXCR6 marks a novel subset of T-betloEomeshi natural killer cells residing in human liver. Sci Rep, 2016, 6: 26157 CrossRef PubMed ADS Google Scholar

[79] Strunz B., Hengst J., Deterding K., Manns M.P., Cornberg M., Ljunggren H.G., Wedemeyer H., Björkström N.K.. Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity. Nat Commun, 2018, 9: 2275 CrossRef PubMed ADS Google Scholar

[80] Sun C., Fu B., Gao Y., Liao X., Sun R., Tian Z., Wei H.. TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human nk cells contributes to HBV persistence. PLoS Pathog, 2012, 8: e1002594 CrossRef PubMed Google Scholar

[81] Sun R., Gao B.. Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-γ). Gastroenterology, 2004, 127: 1525-1539 CrossRef Google Scholar

[82] Takeda K., Cretney E., Hayakawa Y., Ota T., Akiba H., Ogasawara K., Yagita H., Kinoshita K., Okumura K., Smyth M.J.. TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. Blood, 2005, 105: 2082-2089 CrossRef PubMed Google Scholar

[83] Thimme R., Wieland S., Steiger C., Ghrayeb J., Reimann K.A., Purcell R.H., Chisari F.V.. CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol, 2003, 77: 68-76 CrossRef Google Scholar

[84] Thomas R., Yang X.. NK-DC crosstalk in immunity to microbial infection. J Immunol Res, 2016, 2016: 1-7 CrossRef PubMed Google Scholar

[85] Tian Z., Cao X., Chen Y., Lyu Q.. Regional immunity in tissue homeostasis and diseases. Sci China Life Sci, 2016, 59: 1205-1209 CrossRef PubMed Google Scholar

[86] Tian Z., Chen Y., Gao B.. Natural killer cells in liver disease. Hepatology, 2013, 57: 1654-1662 CrossRef PubMed Google Scholar

[87] Tong S., Liu G., Li M., Li X., Liu Q., Peng H., Li S., Ren H., Yin W.. Natural killer cell activation contributes to hepatitis B viral control in a mouse model. Sci Rep, 2017, 7: 314 CrossRef PubMed ADS Google Scholar

[88] Tsuchida T., Friedman S.L.. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol, 2017, 14: 397-411 CrossRef PubMed Google Scholar

[89] Tu Z., Bozorgzadeh A., Pierce R.H., Kurtis J., Crispe I.N., Orloff M.S.. TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med, 2008, 205: 233-244 CrossRef PubMed Google Scholar

[90] Vidal-Castiñeira J.R., López-Vázquez A., Díaz-Peña R., Alonso-Arias R., Martínez-Borra J., Pérez R., Fernández-Suárez J., Melón S., Prieto J., Rodrigo L., et al. Effect of killer immunoglobulin-like receptors in the response to combined treatment in patients with chronic hepatitis C virus infection. J Virol, 2010, 84: 475-481 CrossRef PubMed Google Scholar

[91] Vilarinho S., Ogasawara K., Nishimura S., Lanier L.L., Baron J.L.. Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci USA, 2007, 104: 18187-18192 CrossRef PubMed ADS Google Scholar

[92] Vivier E., Raulet D.H., Moretta A., Caligiuri M.A., Zitvogel L., Lanier L.L., Yokoyama W.M., Ugolini S.. Innate or adaptive immunity? The example of natural killer cells. Science, 2011, 331: 44-49 CrossRef PubMed ADS Google Scholar

[93] Waggoner S.N., Cornberg M., Selin L.K., Welsh R.M.. Natural killer cells act as rheostats modulating antiviral T cells. Nature, 2011, 481: 394-398 CrossRef PubMed ADS Google Scholar

[94] Wensveen F.M., Jelenčić V., Valentić S., Šestan M., Wensveen T.T., Theurich S., Glasner A., Mendrila D., Štimac D., Wunderlich F.T., et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol, 2015, 16: 376-385 CrossRef PubMed Google Scholar

[95] Wisse E., van't Noordende J.M., van der Meulen J., Daems W.T.. The pit cell: description of a new type of cell occurring in rat liver sinusoids and peripheral blood. Cell Tissue Res, 1976, 173: 423-435 CrossRef Google Scholar

[96] Wu X., Chen Y., Wei H., Sun R., Tian Z.. Development of murine hepatic NK cells during ontogeny: comparison with spleen NK cells. Clinical Dev Immunol, 2012, 2012: 1-12 CrossRef PubMed Google Scholar

[97] Wu X., Tian Z.. Gut-liver axis: gut microbiota in shaping hepatic innate immunity. Sci China Life Sci, 2017, 60: 1191-1196 CrossRef PubMed Google Scholar

[98] Xu L., Yin W., Sun R., Wei H., Tian Z.. Kupffer cell-derived IL-10 plays a key role in maintaining humoral immune tolerance in hepatitis B virus-persistent mice. Hepatology, 2014, 59: 443-452 CrossRef PubMed Google Scholar

[99] Yang P.L., Althage A., Chung J., Chisari F.V.. Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection. Proc Natl Acad Sci USA, 2002, 99: 13825-13830 CrossRef PubMed ADS Google Scholar

[100] Zhang Z., Zhang S., Zou Z., Shi J., Zhao J., Fan R., Qin E., Li B., Li Z., Xu X., et al. Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients. Hepatology, 2011, 53: 73-85 CrossRef PubMed Google Scholar

[101] Zheng B., Zhu Y.J., Wang H.Y., Chen L.. Gender disparity in hepatocellular carcinoma (HCC): multiple underlying mechanisms. Sci China Life Sci, 2017, 60: 575-584 CrossRef PubMed Google Scholar

[102] Zheng M., Sun R., Wei H., Tian Z.. NK cells help induce anti–hepatitis B virus CD8+ T cell immunity in mice. J Immunol, 2016, 196: 4122-4131 CrossRef PubMed Google Scholar

[103] Zheng Q., Zhu Y.Y., Chen J., Ye Y.B., Li J.Y., Liu Y.R., Hu M.L., Zheng Y.C., Jiang J.J.. Activated natural killer cells accelerate liver damage in patients with chronic hepatitis B virus infection. Clin Exp Immunol, 2015, 180: 499-508 CrossRef PubMed Google Scholar

[104] Zheng S.J., Wang P., Tsabary G., Chen Y.H.. Critical roles of TRAIL in hepatic cell death and hepatic inflammation. J Clin Invest, 2004, 113: 58-64 CrossRef Google Scholar

[105] Zou Y., Chen T., Han M., Wang H., Yan W., Song G., Wu Z., Wang X., Zhu C., Luo X., et al. Increased killing of liver NK cells by Fas/Fas ligand and NKG2D/NKG2D ligand contributes to hepatocyte necrosis in virus-induced liver failure. J Immunol, 2010, 184: 466-475 CrossRef Google Scholar

  • Figure 1

    NK cell dysfunction during chronic HBV infection. During chronic HBV infection, the immunosuppressive cytokines such as IL-10 and TGF-β are elevated, which induces down-regulation of activating receptors and up-regulation of inhibitory receptors on NK cells. The imbalance of NK cell receptors is accompanied by NK cell dysfunction. NK cells display decreased IFN-γ production, thus impairing the non-cytolytic antiviral function of NK cells, and acquire the ability to secrete IL-10, which inhibits T cell activation. Conserved or increased cytotoxicity of NK cells in chronic HBV infection contributes to liver injury and viral persistence by killing hepatocytes and effector T cells.

Copyright 2019 Science China Press Co., Ltd. 《中国科学》杂志社有限责任公司 版权所有

京ICP备18024590号-1