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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2018, Vol. 12 Issue (3) : 269-279    https://doi.org/10.1007/s11684-018-0621-4
REVIEW |
Natural killer cells in liver diseases
Meijuan Zheng1(), Haoyu Sun2, Zhigang Tian2,3
1. Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
2. Institute of Immunology, Key Laboratory of Innate Immunity and Chronic Disease of Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China
3. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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Abstract

The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute inflammation, chronic infection, autoimmune disease, and tumors. The liver contains a large proportion of natural killer (NK) cells, which exhibit heterogeneity in phenotypic and functional characteristics. NK cell activation, well known for its role in the immune surveillance against tumor and pathogen-infected cells, depends on the balance between numerous activating and inhibitory signals. In addition to the innate direct “killer” functions, NK cell activity contributes to regulate innate and adaptive immunity (helper or regulator). Under the setting of liver diseases, NK cells are of great importance for stimulating or inhibiting immune responses, leading to either immune activation or immune tolerance. Here, we focus on the relationship between NK cell biology, such as their phenotypic features and functional diversity, and liver diseases.

Keywords natural killer cell      phenotype      immune activation      immune tolerance      liver diseases     
Corresponding Authors: Meijuan Zheng   
Just Accepted Date: 12 February 2018   Online First Date: 17 April 2018    Issue Date: 04 May 2018
 Cite this article:   
Meijuan Zheng,Haoyu Sun,Zhigang Tian. Natural killer cells in liver diseases[J]. Front. Med., 2018, 12(3): 269-279.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0621-4
http://academic.hep.com.cn/fmd/EN/Y2018/V12/I3/269
Fig.1  NK cell exhaustion may be the prelude of CD8+ T cell exhaustion. In chronic infection and HCC, effector NK cells become exhausted with increased expressions of inhibitory receptors, such as Tim-3, NKG2A, and PD-1; decreased expressions of activating receptors including NKG2D and NKp30; and decreased expressions of transcription factors, such as and T-bet. And exhausted NK cells may lead to CD8+ T cell exhaustion in chronic infection and tumor conditions.
Fig.2  NK cell activity in liver immunology. NK cells activate T cells through either direct or indirect regulatory mechanisms, leading to liver immunity in acute infection, inflammation, and autoimmune disease. Under chronic infection and tumor conditions, NK cells negatively regulate T cell immunity and induce anergic T cells and Treg cells via direct or indirect mechanisms, which maintain liver tolerance. And NK cell exhaustion may be involved in liver tolerance and associated with exhausted CD8+ T cells in chronic liver disease.
1 Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol 2009; 27(1): 147–163
https://doi.org/10.1146/annurev.immunol.021908.132629 pmid: 19302037
2 Calne RY, Sells RA, Pena JR, Davis DR, Millard PR, Herbertson BM, Binns RM, Davies DA. Induction of immunological tolerance by porcine liver allografts. Nature 1969; 223(5205): 472–476
https://doi.org/10.1038/223472a0 pmid: 4894426
3 Qian S, Demetris AJ, Murase N, Rao AS, Fung JJ, Starzl TE. Murine liver allograft transplantation: tolerance and donor cell chimerism. Hepatology 1994; 19(4): 916–924
https://doi.org/10.1002/hep.1840190418 pmid: 8138266
4 Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol 2012; 12(3): 201–213
https://doi.org/10.1038/nri3169 pmid: 22362353
5 Bogdanos DP, Gao B, Gershwin ME. Liver immunology. Compr Physiol 2013; 3(2): 567–598
pmid: 23720323
6 Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology 2006; 43(2 Suppl 1): S54–S62
https://doi.org/10.1002/hep.21060 pmid: 16447271
7 Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008; 9(5): 503–510
https://doi.org/10.1038/ni1582 pmid: 18425107
8 Lanier LL. NK cell recognition. Annu Rev Immunol 2005; 23(1): 225–274
https://doi.org/10.1146/annurev.immunol.23.021704.115526 pmid: 15771571
9 Yokoyama WM, Kim S, French AR. The dynamic life of natural killer cells. Annu Rev Immunol 2004; 22(1): 405–429
https://doi.org/10.1146/annurev.immunol.22.012703.104711 pmid: 15032583
10 Jinushi M, Takehara T, Tatsumi T, Yamaguchi S, Sakamori R, Hiramatsu N, Kanto T, Ohkawa K, Hayashi N. 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 2007; 120(1): 73–82
https://doi.org/10.1111/j.1365-2567.2006.02479.x pmid: 17052247
11 Lassen MG, Lukens JR, Dolina JS, Brown MG, Hahn YS. Intrahepatic IL-10 maintains NKG2A+Ly49− liver NK cells in a functionally hyporesponsive state. J Immunol 2010; 184(5): 2693–2701
https://doi.org/10.4049/jimmunol.0901362 pmid: 20124099
12 Shi CC, Tjwa ET, Biesta PJ, Boonstra A, Xie Q, Janssen HL, Woltman AM. Hepatitis B virus suppresses the functional interaction between natural killer cells and plasmacytoid dendritic cells. J Viral Hepat 2012; 19(2): e26–e33
https://doi.org/10.1111/j.1365-2893.2011.01496.x pmid: 22239523
13 Tu Z, Bozorgzadeh A, Pierce RH, Kurtis J, Crispe IN, Orloff MS. TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med 2008; 205(1): 233–244
https://doi.org/10.1084/jem.20072195 pmid: 18195076
14 Knolle PA, Gerken G. Local control of the immune response in the liver. Immunol Rev 2000; 174(1): 21–34
https://doi.org/10.1034/j.1600-0528.2002.017408.x pmid: 10807504
15 Gao B. Basic liver immunology. Cell Mol Immunol 2016; 13(3): 265–266
https://doi.org/10.1038/cmi.2016.09 pmid: 27041634
16 Bowen DG, McCaughan GW, Bertolino P. Intrahepatic immunity: a tale of two sites? Trends Immunol 2005; 26(10): 512–517
https://doi.org/10.1016/j.it.2005.08.005 pmid: 16109501
17 Yoneyama H, Ichida T. Recruitment of dendritic cells to pathological niches in inflamed liver. Med Mol Morphol 2005; 38(3): 136–141
https://doi.org/10.1007/s00795-005-0289-0 pmid: 16170461
18 Grant AJ, Goddard S, Ahmed-Choudhury J, Reynolds G, Jackson DG, Briskin M, Wu L, Hübscher SG, Adams DH. Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease. Am J Pathol 2002; 160(4): 1445–1455
https://doi.org/10.1016/S0002-9440(10)62570-9 pmid: 11943728
19 Schildberg FA, Hegenbarth SI, Schumak B, Scholz K, Limmer A, Knolle PA. Liver sinusoidal endothelial cells veto CD8 T cell activation by antigen-presenting dendritic cells. Eur J Immunol 2008; 38(4): 957–967
https://doi.org/10.1002/eji.200738060 pmid: 18383043
20 Bertolino P, Bowen DG, McCaughan GW, Fazekas de St Groth B. Antigen-specific primary activation of CD8+ T cells within the liver. J Immunol 2001; 166(9): 5430–5438
https://doi.org/10.4049/jimmunol.166.9.5430 pmid: 11313380
21 Bertolino P, Trescol-Biémont MC, Rabourdin-Combe C. Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival. Eur J Immunol 1998; 28(1): 221–236
https://doi.org/10.1002/(SICI)1521-4141(199801)28:01<221::AID-IMMU221>3.0.CO;2-F pmid: 9485202
22 Zheng M, Yu J, Tian Z. Characterization of the liver-draining lymph nodes in mice and their role in mounting regional immunity to HBV. Cell Mol Immunol 2013; 10(2): 143–150
https://doi.org/10.1038/cmi.2012.59 pmid: 23376862
23 Barbier L, Tay SS, McGuffog C, Triccas JA, McCaughan GW, Bowen DG, Bertolino P. Two lymph nodes draining the mouse liver are the preferential site of DC migration and T cell activation. J Hepatol 2012; 57(2): 352–358
https://doi.org/10.1016/j.jhep.2012.03.023 pmid: 22542491
24 Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol 2001; 22(11): 633–640
https://doi.org/10.1016/S1471-4906(01)02060-9 pmid: 11698225
25 Yu J, Mao HC, Wei M, Hughes T, Zhang J, Park IK, Liu S, McClory S, Marcucci G, Trotta R, Caligiuri MA. CD94 surface density identifies a functional intermediary between the CD56bright and CD56dim human NK-cell subsets. Blood 2010; 115(2): 274–281
https://doi.org/10.1182/blood-2009-04-215491 pmid: 19897577
26 Björkström NK, Riese P, Heuts F, Andersson S, Fauriat C, Ivarsson MA, Björklund AT, Flodström-Tullberg M, Michaëlsson J, Rottenberg ME, Guzmán CA, Ljunggren HG, Malmberg KJ. Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education. Blood 2010; 116(19): 3853–3864
https://doi.org/10.1182/blood-2010-04-281675 pmid: 20696944
27 Lopez-Vergès S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H, Norris PJ, Nixon DF, Lanier LL. CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset. Blood 2010; 116(19): 3865–3874
https://doi.org/10.1182/blood-2010-04-282301 pmid: 20733159
28 Juelke K, Killig M, Luetke-Eversloh M, Parente E, Gruen J, Morandi B, Ferlazzo G, Thiel A, Schmitt-Knosalla I, Romagnani C. CD62L expression identifies a unique subset of polyfunctional CD56dim NK cells. Blood 2010; 116(8): 1299–1307
https://doi.org/10.1182/blood-2009-11-253286 pmid: 20505160
29 Peritt D, Robertson S, Gri G, Showe L, Aste-Amezaga M, Trinchieri G. Differentiation of human NK cells into NK1 and NK2 subsets. J Immunol 1998; 161(11): 5821–5824
pmid: 9834059
30 Fu B, Tian Z, Wei H. Subsets of human natural killer cells and their regulatory effects. Immunology 2014; 141(4): 483–489
https://doi.org/10.1111/imm.12224 pmid: 24303897
31 Chiossone L, Chaix J, Fuseri N, Roth C, Vivier E, Walzer T. Maturation of mouse NK cells is a 4-stage developmental program. Blood 2009; 113(22): 5488–5496
https://doi.org/10.1182/blood-2008-10-187179 pmid: 19234143
32 Fu B, Wang F, Sun R, Ling B, Tian Z, Wei H. CD11b and CD27 reflect distinct population and functional specialization in human natural killer cells. Immunology 2011; 133(3): 350–359
https://doi.org/10.1111/j.1365-2567.2011.03446.x pmid: 21506999
33 Erick TK, Brossay L. Phenotype and functions of conventional and non-conventional NK cells. Curr Opin Immunol 2016; 38: 67–74
https://doi.org/10.1016/j.coi.2015.11.007 pmid: 26706497
34 Sojka DK, Tian Z, Yokoyama WM. Tissue-resident natural killer cells and their potential diversity. Semin Immunol 2014; 26(2): 127–131
https://doi.org/10.1016/j.smim.2014.01.010 pmid: 24548893
35 Sojka DK, Plougastel-Douglas B, Yang L, Pak-Wittel MA, Artyomov MN, Ivanova Y, Zhong C, Chase JM, Rothman PB, Yu J, Riley JK, Zhu J, Tian Z, Yokoyama WM. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. eLife 2014; 3e01659
36 Doisne JM, Balmas E, Boulenouar S, Gaynor LM, Kieckbusch J, Gardner L, Hawkes DA, Barbara CF, Sharkey AM, Brady HJ, Brosens JJ, Moffett A, Colucci F. Composition, development, and function of uterine innate lymphoid cells. J Immunol 2015; 195(8): 3937–3945
https://doi.org/10.4049/jimmunol.1500689 pmid: 26371244
37 Victorino F, Sojka DK, Brodsky KS, McNamee EN, Masterson JC, Homann D, Yokoyama WM, Eltzschig HK, Clambey ET. Tissue-resident NK cells mediate ischemic kidney injury and are not depleted by anti-Asialo-GM1 antibody. J Immunol 2015; 195(10): 4973–4985
https://doi.org/10.4049/jimmunol.1500651 pmid: 26453755
38 Peng H, Jiang X, Chen Y, Sojka DK, Wei H, Gao X, Sun R, Yokoyama WM, Tian Z. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest 2013; 123(4): 1444–1456
https://doi.org/10.1172/JCI66381 pmid: 23524967
39 Han Q, Zhang C, Zhang J, Tian Z. The role of innate immunity in HBV infection. Semin Immunopathol 2013; 35(1): 23–38
https://doi.org/10.1007/s00281-012-0331-y pmid: 22814721
40 Sun H, Sun C, Tian Z, Xiao W. NK cells in immunotolerant organs. Cell Mol Immunol 2013; 10(3): 202–212
https://doi.org/10.1038/cmi.2013.9 pmid: 23563087
41 Peng H, Wisse E, Tian Z. Liver natural killer cells: subsets and roles in liver immunity. Cell Mol Immunol 2016; 13(3): 328–336
https://doi.org/10.1038/cmi.2015.96 pmid: 26639736
42 Walch M, Dotiwala F, Mulik S, Thiery J, Kirchhausen T, Clayberger C, Krensky AM, Martinvalet D, Lieberman J. Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes. Cell 2014; 157(6): 1309–1323
https://doi.org/10.1016/j.cell.2014.03.062 pmid: 24906149
43 Peppa D, Gill US, Reynolds G, Easom NJ, Pallett LJ, Schurich A, Micco L, Nebbia G, Singh HD, Adams DH, Kennedy PT, Maini MK. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med 2013; 210(1): 99–114
https://doi.org/10.1084/jem.20121172 pmid: 23254287
44 Krueger PD, Narayanan S, Surette FA, Brown MG, Sung SJ, Hahn YS. Murine liver-resident group 1 innate lymphoid cells regulate optimal priming of anti-viral CD8+ T cells. J Leukoc Biol 2017; 101(1): 329–338
https://doi.org/10.1189/jlb.3A0516-225R pmid: 27493244
45 Shi FD, Ljunggren HG, La Cava A, Van Kaer L. Organ-specific features of natural killer cells. Nat Rev Immunol 2011; 11(10): 658–671
https://doi.org/10.1038/nri3065 pmid: 21941294
46 Crome SQ, Lang PA, Lang KS, Ohashi PS. Natural killer cells regulate diverse T cell responses. Trends Immunol 2013; 34(7): 342–349
https://doi.org/10.1016/j.it.2013.03.002 pmid: 23601842
47 Zhang C, Zhang J, Tian Z. The regulatory effect of natural killer cells: do “NK-reg cells” exist? Cell Mol Immunol 2006; 3(4): 241–254
pmid: 16978532
48 Schafer JL, Müller-Trutwin MC, Reeves RK. NK cell exhaustion: bad news for chronic disease? Oncotarget 2015; 6(26): 21797–21798
https://doi.org/10.18632/oncotarget.5490 pmid: 26392410
49 Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 2013; 31(1): 227–258
https://doi.org/10.1146/annurev-immunol-020711-075005 pmid: 23516982
50 Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 2008; 9(5): 495–502
https://doi.org/10.1038/ni1581 pmid: 18425106
51 Watzl C, Long EO. Signal transduction during activation and inhibition of natural killer cells. Curr Protoc Immunol 2010; Chapter 11 Unit 11 19B
52 Tian Z, Chen Y, Gao B. Natural killer cells in liver disease. Hepatology 2013; 57(4): 1654–1662
https://doi.org/10.1002/hep.26115 pmid: 23111952
53 Robinson MW, Harmon C, O’Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol 2016; 13(3): 267–276
https://doi.org/10.1038/cmi.2016.3 pmid: 27063467
54 Bertoletti A, Wang FS. Overview of the special issue on HBV immunity. Cell Mol Immunol 2015; 12(3): 253–254
https://doi.org/10.1038/cmi.2015.24 pmid: 25864914
55 Timm J, Walker CM. Mutational escape of CD8+ T cell epitopes: implications for prevention and therapy of persistent hepatitis virus infections. Med Microbiol Immunol (Berl) 2015; 204(1): 29–38
https://doi.org/10.1007/s00430-014-0372-z pmid: 25537849
56 Shuai Z, Leung MW, He X, Zhang W, Yang G, Leung PS, Eric Gershwin M. Adaptive immunity in the liver. Cell Mol Immunol 2016; 13(3): 354–368
https://doi.org/10.1038/cmi.2016.4 pmid: 26996069
57 Billerbeck E, Wolfisberg R, Fahnoe U, Xiao JW, Quirk C, Luna JM, Cullen JM, Hartlage AS, Chiriboga L, Ghoshal K, Lipkin WI, Bukh J, Scheel TKH, Kapoor A, Rice CM. Mouse models of acute and chronic hepacivirus infection. Science 2017; 357(6347): 204–208
https://doi.org/10.1126/science.aal1962 pmid: PMID:28706073
58 Fu QX, Yan SD, Wang LC, Duan XG, Wang L, Wang Y, Wu T, Wang XH, An J, Zhang YL, Zhou QQ, Zhan LS. Hepatic NK cell-mediated hypersensitivity to ConA-induced liver injury in mouse liver expressing hepatitis C virus polyprotein. Oncotarget 2017; 8(32): 52178–52192
https://doi.org/10.18632/oncotarget.11052 pmid: PMID:28881722
59 Tjwa ETTL, van Oord GW, Hegmans JP, Janssen HLA, Woltman AM. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol 2011; 54(2): 209–218
https://doi.org/10.1016/j.jhep.2010.07.009 pmid: 21095036
60 Oliviero B, Varchetta S, Paudice E, Michelone G, Zaramella M, Mavilio D, De Filippi F, Bruno S, Mondelli MU. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 2009; 137(3): 1151–1160.e7
https://doi.org/10.1053/j.gastro.2009.05.047 pmid: 19470388
61 Shimoda S, Harada K, Niiro H, Shirabe K, Taketomi A, Maehara Y, Tsuneyama K, Nakanuma Y, Leung P, Ansari AA, Gershwin ME, Akashi K. Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis. Hepatology 2011; 53(4): 1270–1281
https://doi.org/10.1002/hep.24194 pmid: 21400555
62 Hudspeth K, Pontarini E, Tentorio P, Cimino M, Donadon M, Torzilli G, Lugli E, Della Bella S, Gershwin ME, Mavilio D. The role of natural killer cells in autoimmune liver disease: a comprehensive review. J Autoimmun 2013; 46: 55–65
https://doi.org/10.1016/j.jaut.2013.07.003 pmid: 23880068
63 Cai L, Zhang Z, Zhou L, Wang H, Fu J, Zhang S, Shi M, Zhang H, Yang Y, Wu H, Tien P, Wang FS. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol 2008; 129(3): 428–437
https://doi.org/10.1016/j.clim.2008.08.012 pmid: 18824414
64 Horst AK, 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(3): 277–292
https://doi.org/10.1038/cmi.2015.112 pmid: 27041638
65 Golden-Mason L, Rosen HR. Natural killer cells: multifaceted players with key roles in hepatitis C immunity. Immunol Rev 2013; 255(1): 68–81
https://doi.org/10.1111/imr.12090 pmid: 23947348
66 Serti E, Chepa-Lotrea X, Kim YJ, Keane M, Fryzek N, Liang TJ, Ghany M, Rehermann B. Successful interferon-free therapy of chronic hepatitis C virus infection normalizes natural killer cell function. Gastroenterology 2015; 149(1):190–200.e2
https://doi.org/10.1053/j.gastro.2015.03.004 pmid: PMID: 25754160
67 Zhao J, Li Y, Jin L, Zhang S, Fan R, Sun Y, Zhou C, Shang Q, Li W, Zhang Z, Wang FS. Natural killer cells are characterized by the concomitantly increased interferon-g and cytotoxicity in acute resolved hepatitis B patients. PLoS One 2012; 7(11): e49135
https://doi.org/10.1371/journal.pone.0049135 pmid: 23133672
68 Golden-Mason L, Cox AL, Randall JA, Cheng L, Rosen HR. Increased natural killer cell cytotoxicity and NKp30 expression protects against hepatitis C virus infection in high-risk individuals and inhibits replication in vitro. Hepatology 2010; 52(5): 1581–1589
https://doi.org/10.1002/hep.23896 pmid: 20812318
69 Knapp S, Warshow U, Hegazy D, Brackenbury L, Guha IN, Fowell A, Little AM, Alexander GJ, Rosenberg WM, Cramp ME, Khakoo SI. Consistent beneficial effects of killer cell immunoglobulin-like receptor 2DL3 and group 1 human leukocyte antigen-C following exposure to hepatitis C virus. Hepatology 2010; 51(4): 1168–1175
https://doi.org/10.1002/hep.23477 pmid: 20077564
70 Abdelrahman MM, Fawzy IO, Bassiouni AA, Gomaa AI, Esmat G, Waked I, Abdelaziz AI. Enhancing NK cell cytotoxicity by miR-182 in hepatocellular carcinoma. Hum Immunol 2016; 77(8): 667–673
https://doi.org/10.1016/j.humimm.2016.04.020 pmid: 27262453
71 Lasfar A, de laTorre A, Abushahba W, Cohen-Solal KA, Castaneda I, Yuan Y, Reuhl K, Zloza A, Raveche E, Laskin DL, Kotenko SV. Concerted action of IFN-α and IFN-l induces local NK cell immunity and halts cancer growth. Oncotarget 2016; 7(31): 49259–49267
https://doi.org/10.18632/oncotarget.10272 pmid: 27363032
72 Maini MK, Peppa D. NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol 2013; 4: 57
https://doi.org/10.3389/fimmu.2013.00057 pmid: 23459859
73 Ghosh S, Nandi M, Pal S, Mukhopadhyay D, Chakraborty BC, Khatun M, Bhowmick D, Mondal RK, Das S, Das K, Ghosh R, Banerjee S, Santra A, Chatterjee M, Chowdhury A, Datta S. Natural killer cells contribute to hepatic injury and help in viral persistence during progression of hepatitis B e-antigen-negative chronic hepatitis B virus infection. Clin Microbiol Infect 2016; 22(8):733.e9–733.e19
https://doi.org/10.1016/j.cmi.2016.05.009 pmid: 27208430
74 Zheng Q, Zhu YY, Chen J, Ye YB, Li JY, Liu YR, Hu ML, Zheng YC, Jiang JJ. Activated natural killer cells accelerate liver damage in patients with chronic hepatitis B virus infection. Clin Exp Immunol 2015; 180(3): 499–508
https://doi.org/10.1111/cei.12597 pmid: 25639451
75 Abu-Tair L, Axelrod JH, Doron S, Ovadya Y, Krizhanovsky V, Galun E, Amer J, Safadi R. Natural killer cell-dependent anti-fibrotic pathway in liver injury via Toll-like receptor-9. PLoS One 2013; 8(12): e82571
https://doi.org/10.1371/journal.pone.0082571 pmid: 24340043
76 Glässner A, Eisenhardt M, Krämer B, Körner C, Coenen M, Sauerbruch T, Spengler U, Nattermann J. 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 2012; 92(7): 967–977
https://doi.org/10.1038/labinvest.2012.54 pmid: 22449797
77 Radaeva S, Sun R, Jaruga B, Nguyen VT, 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(2): 435–452
https://doi.org/10.1053/j.gastro.2005.10.055 pmid: 16472598
78 Doherty DG. Immunity, tolerance and autoimmunity in the liver: a comprehensive review. J Autoimmun 2016; 66: 60–75
https://doi.org/10.1016/j.jaut.2015.08.020 pmid: 26358406
79 Tian Z, Gershwin ME, Zhang C. Regulatory NK cells in autoimmune disease. J Autoimmun 2012; 39(3): 206–215
https://doi.org/10.1016/j.jaut.2012.05.006 pmid: 22704425
80 Chuang YH, Lian ZX, Cheng CM, Lan RY, Yang GX, Moritoki Y, Chiang BL, Ansari AA, Tsuneyama K, Coppel RL, Gershwin ME. Increased levels of chemokine receptor CXCR3 and chemokines IP-10 and MIG in patients with primary biliary cirrhosis and their first degree relatives. J Autoimmun 2005; 25(2): 126–132
https://doi.org/10.1016/j.jaut.2005.08.009 pmid: 16243485
81 Liang Y, Yang Z, Li C, Zhu Y, Zhang L, Zhong R. Characterisation of TNF-related apoptosis-inducing ligand in peripheral blood in patients with primary biliary cirrhosis. Clin Exp Med 2008; 8(1): 1–7
https://doi.org/10.1007/s10238-008-0149-z pmid: 18385934
82 Lanier LL. Evolutionary struggles between NK cells and viruses. Nat Rev Immunol 2008; 8(4): 259–268
https://doi.org/10.1038/nri2276 pmid: 18340344
83 Martín-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F. Induced recruitment of NK cells to lymph nodes provides IFN-γ for T(H)1 priming. Nat Immunol 2004; 5(12): 1260–1265
https://doi.org/10.1038/ni1138 pmid: 15531883
84 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(10): 4122–4131
https://doi.org/10.4049/jimmunol.1500846 pmid: 27183639
85 Combe CL, Curiel TJ, Moretto MM, Khan IA. NK cells help to induce CD8+-T-cell immunity against Toxoplasma gondii in the absence of CD4+ T cells. Infect Immun 2005; 73(8): 4913–4921
https://doi.org/10.1128/IAI.73.8.4913-4921.2005 pmid: 16041005
86 Geldhof AB, Van Ginderachter JA, Liu Y, Noël W, Raes G, De Baetselier P. Antagonistic effect of NK cells on alternatively activated monocytes: a contribution of NK cells to CTL generation. Blood 2002; 100(12): 4049–4058
https://doi.org/10.1182/blood-2001-11-0106 pmid: 12393627
87 Allen F, Rauhe P, Askew D, Tong AA, Nthale J, Eid S, Myers JT, Tong C, Huang AY. CCL3 enhances antitumor immune priming in the lymph node via IFN γ with dependency on natural killer cells. Front Immunol 2017; 8 :1390
https://doi.org/10.3389/fimmu.2017.01390 pmid: PMID: 29109732
88 Adam C, King S, Allgeier T, Braumüller H, Lüking C, Mysliwietz J, Kriegeskorte A, Busch DH, Röcken M, Mocikat R. DC-NK cell cross talk as a novel CD4+ T-cell-independent pathway for antitumor CTL induction. Blood 2005; 106(1): 338–344
https://doi.org/10.1182/blood-2004-09-3775 pmid: 15769894
89 Yuan D. Interactions between NK cells and B lymphocytes. Adv Immunol 2004; 84: 1–42
https://doi.org/10.1016/S0065-2776(04)84001-X pmid: 15246249
90 Krebs P, Barnes MJ, Lampe K, Whitley K, Bahjat KS, Beutler B, Janssen E, Hoebe K. NK-cell-mediated killing of target cells triggers robust antigen-specific T-cell-mediated and humoral responses. Blood 2009; 113(26): 6593–6602
https://doi.org/10.1182/blood-2009-01-201467 pmid: 19406986
91 Li F, Tian Z. The liver works as a school to educate regulatory immune cells. Cell Mol Immunol 2013; 10(4): 292–302
https://doi.org/10.1038/cmi.2013.7 pmid: 23604044
92 Yang Y, Han Q, Hou Z, Zhang C, Tian Z, Zhang J. Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction. Cell Mol Immunol 2017; 14(5): 465–475
https://doi.org/10.1038/cmi.2016.24 pmid: 27238466
93 Zhang QF, Yin WW, Xia Y, Yi YY, He QF, Wang X, Ren H, Zhang DZ. Liver-infiltrating CD11b−€CD27€− NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression. Cell Mol Immunol 2017; 14(10): 819–829
pmid: 27321064
94 Cai L, Zhang Z, Zhou L, Wang H, Fu J, Zhang S, Shi M, Zhang H, Yang Y, Wu H, Tien P, Wang FS. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin Immunol 2008; 129(3): 428–437
https://doi.org/10.1016/j.clim.2008.08.012 pmid: 18824414
95 Chen T, Zhu L, Shi AC, Ding L, Zhang XP, Tan ZM, Guo W, Yan WM, Han MF, Jia JD, Luo XP, Schuppan D, Ning Q. Functional restoration of CD56bright NK cells facilitates immune control via IL-15 and NKG2D in patients under antiviral treatment for chronic hepatitis B. Hepatol Int 2017; 11(5): 419–428
https://doi.org/10.1007/s12072-017-9803-4 pmid: 28639033
96 Podhorzer A, Dirchwolf M, Machicote A, Belen S, Montal S, Paz S, Fainboim H, Podesta L G, Fainboim L. The clinical features of patients with chronic hepatitis C virus infections are associated with killer cell immunoglobulin-like receptor genes and their expression on the surface of natural killer cells. Front Immunol 2018; 8:1912
https://doi.org/10.3389/fimmu.2017.01912 pmid: PMID:29354127
97 Tatsumi T, Takehara T. Impact of natural killer cells on chronic hepatitis C and hepatocellular carcinoma. Hepatol Res 2016; 46(5): 416–422
https://doi.org/10.1111/hepr.12619 pmid: PMID:26574168
98 Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol 2001; 1(1): 41–49
https://doi.org/10.1038/35095564 pmid: 11905813
99 Sun C, Sun H, Zhang C, Tian Z. NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma. Cell Mol Immunol 2015; 12(3): 292–302
https://doi.org/10.1038/cmi.2014.91 pmid: 25308752
100 Liu KJ, Wang CJ, Chang CJ, Hu HI, Hsu PJ, Wu YC, Bai CH, Sytwu HK, Yen BL. Surface expression of HLA-G is involved in mediating immunomodulatory effects of placenta-derived multipotent cells (PDMCs) towards natural killer lymphocytes. Cell Transplant 2011; 20(11-12): 1721–1730
https://doi.org/10.3727/096368911X580590 pmid: 21669042
101 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. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol 2010; 52(3): 322–329
https://doi.org/10.1016/j.jhep.2009.12.005 pmid: 20133006
102 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(3): e1002594
https://doi.org/10.1371/journal.ppat.1002594 pmid: 22438812
103 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(2): 392–401
https://doi.org/10.1053/j.gastro.2012.10.039 pmid: 23103614
104 Wang JM, Cheng YQ, Shi L, Ying RS, Wu XY, Li GY, Moorman JP, Yao ZQ. KLRG1 negatively regulates natural killer cell functions through the Akt pathway in individuals with chronic hepatitis C virus infection. J Virol 2013; 87(21): 11626–11636
https://doi.org/10.1128/JVI.01515-13 pmid: 23966413
105 Golden-Mason L, Waasdorp Hurtado CE, Cheng L, Rosen HR. Hepatitis C viral infection is associated with activated cytolytic natural killer cells expressing high levels of T cell immunoglobulin- and mucin-domain-containing molecule-3. Clin Immunol 2015; 158(1): 114–125
https://doi.org/10.1016/j.clim.2015.03.008 pmid: 25797693
106 Peppa D, Micco L, Javaid A, Kennedy PT, Schurich A, Dunn C, Pallant C, Ellis G, Khanna P, Dusheiko G, Gilson RJ, Maini MK. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog 2010; 6(12): e1001227
https://doi.org/10.1371/journal.ppat.1001227 pmid: 21187913
107 Sun C, Xu J, Huang Q, Huang M, Wen H, Zhang C, Wang J, Song J, Zheng M, Sun H, Wei H, Xiao W, Sun R, Tian Z. High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer. OncoImmunology 2017; 6(1): e1264562
https://doi.org/10.1080/2162402X.2016.1264562 pmid: 28197391
108 Waggoner SN, Taniguchi RT, Mathew PA, Kumar V, Welsh RM. Absence of mouse 2B4 promotes NK cell-mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. J Clin Invest 2010; 120(6): 1925–1938
https://doi.org/10.1172/JCI41264 pmid: 20440077
109 Soderquest K, Walzer T, Zafirova B, Klavinskis LS, Polić B, Vivier E, Lord GM, Martín-Fontecha A. Cutting edge: CD8+ T cell priming in the absence of NK cells leads to enhanced memory responses. J Immunol 2011; 186(6): 3304–3308
https://doi.org/10.4049/jimmunol.1004122 pmid: 21307295
110 Lang PA, Lang KS, Xu HC, Grusdat M, Parish IA, Recher M, Elford AR, Dhanji S, Shaabani N, Tran CW, Dissanayake D, Rahbar R, Ghazarian M, Brüstle A, Fine J, Chen P, Weaver CT, Klose C, Diefenbach A, Häussinger D, Carlyle JR, Kaech SM, Mak TW, Ohashi PS. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc Natl Acad Sci USA 2012; 109(4): 1210–1215
https://doi.org/10.1073/pnas.1118834109 pmid: 22167808
111 Deniz G, Erten G, Kücüksezer UC, Kocacik D, Karagiannidis C, Aktas E, Akdis CA, Akdis M. Regulatory NK cells suppress antigen-specific T cell responses. J Immunol 2008; 180(2): 850–857
https://doi.org/10.4049/jimmunol.180.2.850 pmid: 18178824
112 Crouse J, Bedenikovic G, Wiesel M, Ibberson M, Xenarios I, Von Laer D, Kalinke U, Vivier E, Jonjic S, Oxenius A. Type I interferons protect T cells against NK cell attack mediated by the activating receptor NCR1. Immunity 2014; 40(6): 961–973
https://doi.org/10.1016/j.immuni.2014.05.003 pmid: 24909889
113 Xu HC, Grusdat M, Pandyra AA, Polz R, Huang J, Sharma P, Deenen R, Köhrer K, Rahbar R, Diefenbach A, Gibbert K, Löhning M, Höcker L, Waibler Z, Häussinger D, Mak TW, Ohashi PS, Lang KS, Lang PA. Type I interferon protects antiviral CD8+ T cells from NK cell cytotoxicity. Immunity 2014; 40(6): 949–960
https://doi.org/10.1016/j.immuni.2014.05.004 pmid: 24909887
114 De Rose V, Cappello P, Sorbello V, Ceccarini B, Gani F, Bosticardo M, Fassio S, Novelli F. IFN-γ inhibits the proliferation of allergen-activated T lymphocytes from atopic, asthmatic patients by inducing Fas/FasL-mediated apoptosis. J Leukoc Biol 2004; 76(2): 423–432
https://doi.org/10.1189/jlb.0503247 pmid: 15123769
115 Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood 2008; 112(5): 1557–1569
https://doi.org/10.1182/blood-2008-05-078154 pmid: 18725574
116 De Pelsmaeker S, Devriendt B, Leclercq G, Favoreel HW. Porcine NK cells display features associated with antigen-presenting cells. J Leukocyte Biol 2018; 103(1):129–140
https://doi.org/10.1002/JLB.4A0417-163RR PMID:29345060
117 Iraolagoitia XLR, Spallanzani RG, Torres NI, Araya RE, Ziblat A, Domaica CI, Sierra JM, Nunez SY, Secchiari F, Gajewski TF, Zwirner NW, Fuertes MB. NK cells restrain spontaneous antitumor CD8+ T cell priming through PD-1/PD-L1 interactions with dendritic cells. J Immunol 2016; 197(3):953–961
https://doi.org/10.4049/jimmunol.1502291 pmid: PMID:27342842
118 Meazza R, Falco M, Marcenaro S, Loiacono F, Canevali P, Bellora F, Tuberosa C, Locatelli F, Micalizzi C, Moretta A, Mingari MC, Moretta L, Arico M, Bottino C, Pende D. Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients. Eur J Immunol 2017; 47(6):1051–1061
https://doi.org/10.1002/eji.201646885 pmid: PMID:28386908
119 Cairo C, Surendran N, Harris KM, Mazan-Mamczarz K, Sakoda Y, Diaz-Mendez F, Tamada K, Gartenhaus RB, Mann DL, Pauza CD. Vγ2Vδ2 T-cell co-stimulation increases natural killer cell killing of monocyte-derived dendritic cells. Immunology 2015; 144(3): 422–430
https://doi.org/10.1111/imm.12386
120 Andrews DM, Estcourt MJ, Andoniou CE, Wikstrom ME, Khong A, Voigt V, Fleming P, Tabarias H, Hill GR, van der Most RG, Scalzo AA, Smyth MJ, Degli-Esposti MA. Innate immunity defines the capacity of antiviral T cells to limit persistent infection. J Exp Med 2010; 207(6): 1333–1343
https://doi.org/10.1084/jem.20091193 pmid: 20513749
121 Cook KD, Whitmire JK. The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection. J Immunol 2013; 190(2): 641–649
https://doi.org/10.4049/jimmunol.1202448 pmid: 23241878
122 Schafer JL, Li H, Evans TI, Estes JD, Reeves RK. Accumulation of cytotoxic CD16+ NK cells in simian immunodeficiency virus-infected lymph nodes associated with in situ differentiation and functional anergy. J Virol 2015; 89(13): 6887–6894
https://doi.org/10.1128/JVI.00660-15 pmid: 25903330
123 Gill S, Vasey AE, De Souza A, Baker J, Smith AT, Kohrt HE, Florek M, Gibbs KD Jr, Tate K, Ritchie DS, Negrin RS. Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells. Blood 2012; 119(24): 5758–5768
https://doi.org/10.1182/blood-2012-03-415364 pmid: 22544698
124 Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, Gonçalves A, André P, Romagné F, Thibault G, Viens P, Birnbaum D, Bertucci F, Moretta A, Olive D. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest 2011; 121(9): 3609–3622
https://doi.org/10.1172/JCI45816 pmid: 21841316
125 da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK, Osman I, Bhardwaj N. Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res 2014; 2(5): 410–422
https://doi.org/10.1158/2326-6066.CIR-13-0171 pmid: 24795354
126 Odorizzi PM, Pauken KE, Paley MA, Sharpe A, Wherry EJ. Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J Exp Med 2015; 212(7): 1125–1137
https://doi.org/10.1084/jem.20142237 pmid: 26034050
127 Lee SH, Kim KS, Fodil-Cornu N, Vidal SM, Biron CA. Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection. J Exp Med 2009; 206(10): 2235–2251
https://doi.org/10.1084/jem.20082387 pmid: 19720840
128 Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MB. Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 2006; 12(11): 1301–1309
https://doi.org/10.1038/nm1492 pmid: 17041596
129 Harmon C, Robinson MW, Fahey R, Whelan S, Houlihan DD, Geoghegan J, O’Farrelly C. Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver. Eur J Immunol 2016; 46(9): 2111–2120
https://doi.org/10.1002/eji.201646559 pmid: 27485474
130 Stegmann KA, Robertson F, Hansi N, Gill U, Pallant C, Christophides T, Pallett LJ, Peppa D, Dunn C, Fusai G, Male V, Davidson BR, Kennedy P, Maini MK. CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver. Sci Rep-Uk 2016; 6:26157
https://doi.org/DOI: 10.1038/srep26157
131 Hudspeth K, Donadon M, Cimino M, Pontarini E, Tentorio P, Preti M, Hong M, Bertoletti A, Bicciato S, Invernizzi P, Lugli E, Torzilli G, Gershwin ME, Mavilio D. Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J Autoimmun 2016; 66: 40–50
https://doi.org/10.1016/j.jaut.2015.08.011 pmid: 26330348
132 Cuff AO, Robertson FP, Stegmann KA, Pallett LJ, Maini MK, Davidson BR, Male V. Eomeshi NK cells in human liver are long-lived and do not recirculate but can be replenished from the circulation. J Immunol 2016; 197(11): 4283–4291
https://doi.org/10.4049/jimmunol.1601424 pmid: 27798170
133 Lugli E, Hudspeth K, Roberto A, Mavilio D. Tissue-resident and memory properties of human T-cell and NK-cell subsets. Eur J Immunol 2016; 46(8): 1809–1817
https://doi.org/10.1002/eji.201545702 pmid: 27431095
134 Paust S, Gill HS, Wang BZ, Flynn MP, Moseman EA, Senman B, Szczepanik M, Telenti A, Askenase PW, Compans RW, von Andrian UH. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat Immunol 2010; 11(12): 1127–1135
https://doi.org/10.1038/ni.1953 pmid: 20972432
135 Sojka DK, Plougastel-Douglas B, Yang L, Pak-Wittel MA, Artyomov MN, Ivanova Y, Zhong C, Chase JM, Rothman PB, Yu J, Riley JK, Zhu J, Tian Z, Yokoyama WM. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. eLife 2014; 3: e01659
https://doi.org/10.7554/eLife.01659 pmid: 24714492
136 Yu M, Li ZH. Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic approaches. Front Med 2017; 11(4): 509–521
https://doi.org/10.1007/s11684-017-0546-3 pmid: PMID:28780700
137 BoudreauJE, Hsu KC. Natural killer cell education and the response to infection and cancer therapy: stay tuned. Trends Immunol 2018 Jan 31. pii: S1471-4906(17)30230-2. [Epub ahead of print]
https://doi.org/10.1016/j.it.2017.12.001 pmid: 29397297
138 Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol 2013; 10(3): 230–252
https://doi.org/10.1038/cmi.2013.10 pmid: 23604045
139 Serti E, Park H, Keane M, O’Keefe AC, Rivera E, Liang TJ, Ghany M, Rehermann B. Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNα. Gut 2017; 66(4): 724–735
https://doi.org/10.1136/gutjnl-2015-310033 pmid: 26733671
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[2] Jingjing Yan, Shuye Zhang, Jun Sun, Jianqing Xu, Xiaoyang Zhang. Irreversible phenotypic perturbation and functional impairment of B cells during HIV-1 infection[J]. Front. Med., 2017, 11(4): 536-547.
[3] Min Yu, Zonghai Li. Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic approaches[J]. Front. Med., 2017, 11(4): 509-521.
[4] Xuezhong Zhou,Yubing Li,Yonghong Peng,Jingqing Hu,Runshun Zhang,Liyun He,Yinghui Wang,Lijie Jiang,Shiyan Yan,Peng Li,Qi Xie,Baoyan Liu. Clinical phenotype network: the underlying mechanism for personalized diagnosis and treatment of traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 337-346.
[5] Xu Chen, Xiaomao Xu, Fei Xiao. Heterogeneity of chronic obstructive pulmonary disease: from phenotype to genotype[J]. Front Med, 2013, 7(4): 425-432.
[6] Min Cheng, Jian Zhang, Wen Jiang, Yongyan Chen, Zhigang Tian. Natural killer cell lines in tumor immunotherapy[J]. Front Med, 2012, 6(1): 56-66.
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