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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

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Front. Med.    2018, Vol. 12 Issue (3) : 249-261    https://doi.org/10.1007/s11684-018-0622-3
REVIEW
NKT cells in liver diseases
Shasha Zhu1,2, Huimin Zhang1,2, Li Bai1,2()
1. CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China
2. Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei 230027, China
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Abstract

Natural killer T cells are innate-like and tissue-resident lymphocytes, which recognize lipid antigens and are enriched in the liver. Natural killer T cells play important roles in infections, tumors, autoimmune diseases, and metabolic diseases. In this study, we summarize recent findings on biology of natural killer T cells and their roles in hepatitis B virus and hepatitis C virus infection, autoimmune liver diseases, alcoholic liver disease, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Controversial results from previous studies are discussed, and indicate the dynamic alteration in the role of natural killer T cells during the progression of liver diseases, which might be caused by changes in natural killer T subsets, factors skewing cytokine responses, and intercellular crosstalk between natural killer T cells and CD1d-expressing cells or bystander cells.
Keywords natural killer T cells      hepatitis B virus and hepatitis C virus infection      autoimmune liver diseases      alcoholic liver disease      nonalcoholic fatty liver disease      hepatocellular carcinoma     
Corresponding Author(s): Li Bai   
Just Accepted Date: 09 February 2018   Online First Date: 09 April 2018    Issue Date: 04 May 2018
 Cite this article:   
Shasha Zhu,Huimin Zhang,Li Bai. NKT cells in liver diseases[J]. Front. Med., 2018, 12(3): 249-261.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0622-3
https://academic.hep.com.cn/fmd/EN/Y2018/V12/I3/249
Fig.1  Distribution of NKT cell subsets and their characteristics. NKT cells that emigrate from the thymus are mostly developed from a common precursor of CD4+CD8+ double-positive (DP) thymocytes. These double-positive precursors undergo a series of steps that ultimately results in the NKT cell pool with tissue-specific distribution. Hepatic and splenic NKT1 cells are IL-17RB−T-bethighPLZFlow and secrete both IFN-γ and IL-4. The NKT2 defined as GATA3highPLZFhigh populations and NKT17 cells defined as RORγt+PLZFmed populations accumulate in the lung and lymph node, respectively, and both are IL-17RB+. In adipose tissues, NKT10 cells express the transcription factor E4BP4 and mainly secrete IL-10. Moreover, some CD4−CD8− NKT cells are generated from CD4−CD8− (double negative, DN) thymocytes and bypass the DP-stage. The CD4−CD8− NKT cells of DN-stage origin mainly accumulate in the liver and show increased cytotoxicity. NKR, NK lineage receptors, including NK1.1, Ly49, NKG2D, CD94, and DX5.
Fig.2  Crosstalk between NKT cells and other cells in liver diseases. Several factors, including cytokines, antigen structures, and types of antigen presenting cells (APCs), can modulate NKT-cell-mediated immune responses. In the liver, NKT cell activation could lead to fibrosis, ALD, PBC, and NAFLD via activating HSC, B cells, CD8+ T cells, and NK cells, as well as killing hepatocytes through the Fas-FasL pathway. Furthermore, NKT cells are involved in the clearance of HBV, HCV, and HCC by promoting Th1 cytokine production and activation of CD8+ T cells and NK cells. Additionally, NKT cells can inhibit NAFLD by promoting Th2 cytokines, possibly through interactions with M2 macrophages, adipocytes, and hepatocytes. OPN, osteopontin; ALD, alcoholic liver disease; NAFLD, nonalcoholic fatty liver disease; PBC, primary biliary cholangitis; HCC, hepatocellular carcinoma; HSC, hepatic stellate cell; NK, natural killer cells; NKT, natural killer T cells; M2, M2 macrophage.
1 Makino Y, Kanno R, Ito T, Higashino K, Taniguchi M. Predominant expression of invariant Vα14+ TCRα chain in NK1.1+ T cell populations. Int Immunol 1995; 7(7): 1157–1161
https://doi.org/10.1093/intimm/7.7.1157 pmid: 8527413
2 Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong ST, Brenner MB. Recognition of a lipid antigen by CD1-restricted αβ+ T cells. Nature 1994; 372(6507): 691–694
https://doi.org/10.1038/372691a0 pmid: 7527500
3 Godfrey DI, Hammond KJL, Poulton LD, Smyth MJ, Baxter AG. NKT cells: facts, functions and fallacies. Immunol Today 2000; 21(11): 573–583
https://doi.org/10.1016/S0167-5699(00)01735-7 pmid: 11094262
4 Dascher CC, Brenner MB. Evolutionary constraints on CD1 structure: insights from comparative genomic analysis. Trends Immunol 2003; 24(8): 412–418
https://doi.org/10.1016/S1471-4906(03)00179-0 pmid: 12909453
5 Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. NKT cells: what’s in a name? Nat Rev Immunol 2004; 4(3): 231–237
https://doi.org/10.1038/nri1309 pmid: 15039760
6 Brossay L, Chioda M, Burdin N, Koezuka Y, Casorati G, Dellabona P, Kronenberg M. CD1d-mediated recognition of an α-galactosylceramide by natural killer T cells is highly conserved through mammalian evolution. J Exp Med 1998; 188(8): 1521–1528
https://doi.org/10.1084/jem.188.8.1521 pmid: 9782129
7 Godfrey DI, Stankovic S, Baxter AG. Raising the NKT cell family. Nat Immunol 2010; 11(3): 197–206
https://doi.org/10.1038/ni.1841 pmid: 20139988
8 Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007; 25(1): 297–336
https://doi.org/10.1146/annurev.immunol.25.022106.141711 pmid: 17150027
9 Hammond KJL, Pelikan SB, Crowe NY, Randle-Barrett E, Nakayama T, Taniguchi M, Smyth MJ, van Driel IR, Scollay R, Baxter AG, Godfrey DI. NKT cells are phenotypically and functionally diverse. Eur J Immunol 1999; 29(11): 3768–3781
https://doi.org/10.1002/(SICI)1521-4141(199911)29:11<3768::AID-IMMU3768>3.0.CO;2-G pmid: 10556834
10 Akbari O, Stock P, Meyer E, Kronenberg M, Sidobre S, Nakayama T, Taniguchi M, Grusby MJ, DeKruyff RH, Umetsu DT. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med 2003; 9(5): 582–588
https://doi.org/10.1038/nm851 pmid: 12669034
11 Sakuishi K, Oki S, Araki M, Porcelli SA, Miyake S, Yamamura T. Invariant NKT cells biased for IL-5 production act as crucial regulators of inflammation. J Immunol 2007; 179(6): 3452–3462
https://doi.org/10.4049/jimmunol.179.6.3452 pmid: 17785779
12 Cerundolo V, Silk JD, Masri SH, Salio M. Harnessing invariant NKT cells in vaccination strategies. Nat Rev Immunol 2009; 9(1): 28–38
https://doi.org/10.1038/nri2451 pmid: 19079136
13 Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007; 25(1): 297–336
https://doi.org/10.1146/annurev.immunol.25.022106.141711 pmid: 17150027
14 Hegde S, Chen X, Keaton JM, Reddington F, Besra GS, Gumperz JE. NKT cells direct monocytes into a DC differentiation pathway. J Leukoc Biol 2007; 81(5): 1224–1235
https://doi.org/10.1189/jlb.1206718 pmid: 17311932
15 Kitamura H, Ohta A, Sekimoto M, Sato M, Iwakabe K, Nakui M, Yahata T, Meng H, Koda T, Nishimura S, Kawano T, Taniguchi M, Nishimura T. α-Galactosylceramide induces early B-cell activation through IL-4 production by NKT cells. Cell Immunol 2000; 199(1): 37–42
https://doi.org/10.1006/cimm.1999.1602 pmid: 10675273
16 Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, Schmidt R, Harris AL, Old L, Cerundolo V. NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 2003; 171(10): 5140–5147
https://doi.org/10.4049/jimmunol.171.10.5140 pmid: 14607913
17 Eberl G, MacDonald HR. Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells. Eur J Immunol 2000; 30(4): 985–992
https://doi.org/10.1002/(SICI)1521-4141(200004)30:4<985::AID-IMMU985>3.0.CO;2-E pmid: 10760785
18 Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 1997; 278(5343): 1626–1629
https://doi.org/10.1126/science.278.5343.1626 pmid: 9374463
19 Godfrey DI, Stankovic S, Baxter AG. Raising the NKT cell family. Nat Immunol 2010; 11(3): 197–206
https://doi.org/10.1038/ni.1841 pmid: 20139988
20 Godfrey DI, Pellicci DG, Patel O, Kjer-Nielsen L, McCluskey J, Rossjohn J. Antigen recognition by CD1d-restricted NKT T cell receptors. Semin Immunol 2010; 22(2): 61–67
https://doi.org/10.1016/j.smim.2009.10.004 pmid: 19945889
21 Savage PB, Teyton L, Bendelac A. Glycolipids for natural killer T cells. Chem Soc Rev 2006; 35(9): 771–779
https://doi.org/10.1039/b510638a pmid: 16936925
22 Xia C, Yao Q, Schümann J, Rossy E, Chen W, Zhu L, Zhang W, De Libero G, Wang PG. Synthesis and biological evaluation of α-galactosylceramide (KRN7000) and isoglobotrihexosylceramide (iGb3). Bioorg Med Chem Lett 2006; 16(8): 2195–2199
https://doi.org/10.1016/j.bmcl.2006.01.040 pmid: 16458002
23 Stanic AK, De Silva AD, Park JJ, Sriram V, Ichikawa S, Hirabyashi Y, Hayakawa K, Van Kaer L, Brutkiewicz RR, Joyce S. Defective presentation of the CD1d1-restricted natural Vα14Jα18 NKT lymphocyte antigen caused by β-D-glucosylceramide synthase deficiency. Proc Natl Acad Sci USA 2003; 100(4): 1849–1854
https://doi.org/10.1073/pnas.0430327100 pmid: 12576547
24 Brigl M, Tatituri RVV, Watts G F M, Bhowruth V, Leadbetter EA, Barton N, Cohen NR, Hsu FF, Besra GS, Brenner MB. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J Exp Med 2011; 208(6): 1163–1177
https://doi.org/10.1084/jem.20102555 pmid: 21555485
25 Nagarajan NA, Kronenberg M. Invariant NKT cells amplify the innate immune response to lipopolysaccharide. J Immunol 2007; 178(5): 2706–2713
https://doi.org/10.4049/jimmunol.178.5.2706 pmid: 17312112
26 Tupin E, Kinjo Y, Kronenberg M. The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol 2007; 5(6): 405–417
https://doi.org/10.1038/nrmicro1657 pmid: 17487145
27 Paget C, Mallevaey T, Speak AO, Torres D, Fontaine J, Sheehan KCF, Capron M, Ryffel B, Faveeuw C, Leite de Moraes M, Platt F, Trottein F. Activation of invariant NKT cells by toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids. Immunity 2007; 27(4): 597–609
https://doi.org/10.1016/j.immuni.2007.08.017 pmid: 17950005
28 Godfrey DI, Rossjohn J. New ways to turn on NKT cells. J Exp Med 2011; 208(6): 1121–1125
https://doi.org/10.1084/jem.20110983 pmid: 21646400
29 Hermans IF, Silk JD, Gileadi U, Masri SH, Shepherd D, Farrand KJ, Salio M, Cerundolo V. Dendritic cell function can be modulated through cooperative actions of TLR ligands and invariant NKT cells. J Immunol 2007; 178(5): 2721–2729
https://doi.org/10.4049/jimmunol.178.5.2721 pmid: 17312114
30 Baxevanis CN, Gritzapis AD, Papamichail M. In vivo antitumor activity of NKT cells activated by the combination of IL-12 and IL-18. J Immunol 2003; 171(6): 2953–2959
https://doi.org/10.4049/jimmunol.171.6.2953 pmid: 12960319
31 Grela F, Aumeunier A, Bardel E, Van LP, Bourgeois E, Vanoirbeek J, Leite-de-Moraes M, Schneider E, Dy M, Herbelin A, Thieblemont N. The TLR7 agonist R848 alleviates allergic inflammation by targeting invariant NKT cells to produce IFN-γ. J Immunol 2011; 186(1): 284–290
https://doi.org/10.4049/jimmunol.1001348 pmid: 21131420
32 Miyamoto K, Miyake S, Yamamura T. A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells. Nature 2001; 413(6855): 531–534
https://doi.org/10.1038/35097097 pmid: 11586362
33 Yu KOA, Im JS, Molano A, Dutronc Y, Illarionov PA, Forestier C, Fujiwara N, Arias I, Miyake S, Yamamura T, Chang YT, Besra GS, Porcelli SA. Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of α-galactosylceramides. Proc Natl Acad Sci USA 2005; 102(9): 3383–3388
https://doi.org/10.1073/pnas.0407488102 pmid: 15722411
34 Goff RD, Gao Y, Mattner J, Zhou D, Yin N, Cantu C 3rd, Teyton L, Bendelac A, Savage PB. Effects of lipid chain lengths in α-galactosylceramides on cytokine release by natural killer T cells. J Am Chem Soc 2004; 126(42): 13602–13603
https://doi.org/10.1021/ja045385q pmid: 15493902
35 McCarthy C, Shepherd D, Fleire S, Stronge VS, Koch M, Illarionov PA, Bossi G, Salio M, Denkberg G, Reddington F, Tarlton A, Reddy BG, Schmidt RR, Reiter Y, Griffiths GM, van der Merwe PA, Besra GS, Jones EY, Batista FD, Cerundolo V. The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation. J Exp Med 2007; 204(5): 1131–1144
https://doi.org/10.1084/jem.20062342 pmid: 17485514
36 Bai L, Constantinides MG, Thomas SY, Reboulet R, Meng F, Koentgen F, Teyton L, Savage PB, Bendelac A. Distinct APCs explain the cytokine bias of α-galactosylceramide variants in vivo. J Immunol 2012; 188(7): 3053–3061
https://doi.org/10.4049/jimmunol.1102414 pmid: 22393151
37 Oki S, Chiba A, Yamamura T, Miyake S. The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells. J Clin Invest 2004; 113(11): 1631–1640
https://doi.org/10.1172/JCI200420862 pmid: 15173890
38 Hua J, Ma X, Webb T, Potter JJ, Oelke M, Li Z. Dietary fatty acids modulate antigen presentation to hepatic NKT cells in nonalcoholic fatty liver disease. J Lipid Res 2010; 51(7): 1696–1703
https://doi.org/10.1194/jlr.M003004 pmid: 20185414
39 Xie D, Zhu S, Bai L. Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling. Sci China Life Sci 2016; 59(12): 1290–1296
https://doi.org/10.1007/s11427-016-0348-7 pmid: 27995420
40 Apostolou I, Takahama Y, Belmant C, Kawano T, Huerre M, Marchal G, Cui J, Taniguchi M, Nakauchi H, Fournie JJ, Kourilsky P, Gachelin G. Murine natural killer T (NKT) cells contribute to the granulomatous reaction caused by mycobacterial cell walls. Proc Natl Acad Sci USA 1999; 96(9): 5141–5146
https://doi.org/10.1073/pnas.96.9.5141 pmid: 10220432
41 Chackerian A, Alt J, Perera V, Behar SM. Activation of NKT cells protects mice from tuberculosis. Infect Immun 2002; 70(11): 6302–6309
https://doi.org/10.1128/IAI.70.11.6302-6309.2002 pmid: 12379709
42 Opasawatchai A, Matangkasombut P. iNKT cells and their potential lipid ligands during viral infection. Front Immunol 2015; 6: 378
https://doi.org/10.3389/fimmu.2015.00378 pmid: 26257744
43 Tahir SM, Cheng O, Shaulov A, Koezuka Y, Bubley GJ, Wilson SB, Balk SP, Exley MA. Loss of IFN-γ production by invariant NK T cells in advanced cancer. J Immunol 2001; 167(7): 4046–4050
https://doi.org/10.4049/jimmunol.167.7.4046 pmid: 11564825
44 Toura I, Kawano T, Akutsu Y, Nakayama T, Ochiai T, Taniguchi M. Cutting edge: inhibition of experimental tumor metastasis by dendritic cells pulsed with α-galactosylceramide. J Immunol 1999; 163(5): 2387–2391
pmid: 10452972
45 Miyamoto K, Miyake S, Yamamura T. A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells. Nature 2001; 413(6855): 531–534
https://doi.org/10.1038/35097097 pmid: 11586362
46 Singh AK, Wilson MT, Hong S, Olivares-Villagómez D, Du C, Stanic AK, Joyce S, Sriram S, Koezuka Y, Van Kaer L. Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis. J Exp Med 2001; 194(12): 1801–1811
https://doi.org/10.1084/jem.194.12.1801 pmid: 11748281
47 Zhang H, Xue R, Zhu S, Fu S, Chen Z, Zhou R, Tian Z, Bai L. M2-specific reduction of CD1d switches NKT cell-mediated immune responses and triggers metaflammation in adipose tissue. Cell Mol Immunol 2017 Apr 10. [Epub ahead of print] https://doi.org/10.1038/cmi.2017.11
https://doi.org/10.1038/cmi.2017.11 pmid: 28392574
48 Thomas SY, Scanlon ST, Griewank KG, Constantinides MG, Savage AK, Barr KA, Meng F, Luster AD, Bendelac A. PLZF induces an intravascular surveillance program mediated by long-lived LFA-1-ICAM-1 interactions. J Exp Med 2011; 208(6): 1179–1188
https://doi.org/10.1084/jem.20102630 pmid: 21624939
49 Slauenwhite D, Johnston B. Regulation of NKT cell localization in homeostasis and infection. Front Immunol 2015; 6: 255
https://doi.org/10.3389/fimmu.2015.00255 pmid: 26074921
50 Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ, Dustin ML, Littman DR. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol 2005; 3(4): e113
https://doi.org/10.1371/journal.pbio.0030113 pmid: 15799695
51 King IL, Amiel E, Tighe M, Mohrs K, Veerapen N, Besra G, Mohrs M, Leadbetter EA. The mechanism of splenic invariant NKT cell activation dictates localization in vivo. J Immunol 2013; 191(2): 572–582
https://doi.org/10.4049/jimmunol.1300299 pmid: 23785119
52 Barral P, Sánchez-Niño MD, van Rooijen N, Cerundolo V, Batista FD. The location of splenic NKT cells favours their rapid activation by blood-borne antigen. EMBO J 2012; 31(10): 2378–2390
https://doi.org/10.1038/emboj.2012.87 pmid: 22505026
53 Lynch L, Michelet X, Zhang S, Brennan PJ, Moseman A, Lester C, Besra G, Vomhof-Dekrey EE, Tighe M, Koay HF, Godfrey DI, Leadbetter EA, Sant’Angelo DB, von Andrian U, Brenner MB. Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue. Nat Immunol 2015; 16(1): 85–95
https://doi.org/10.1038/ni.3047 pmid: 25436972
54 Scanlon ST, Thomas SY, Ferreira CM, Bai L, Krausz T, Savage PB, Bendelac A. Airborne lipid antigens mobilize resident intravascular NKT cells to induce allergic airway inflammation. J Exp Med 2011; 208(10): 2113–2124
https://doi.org/10.1084/jem.20110522 pmid: 21930768
55 Constantinides MG, Bendelac A. Transcriptional regulation of the NKT cell lineage. Curr Opin Immunol 2013; 25(2): 161–167
https://doi.org/10.1016/j.coi.2013.01.003 pmid: 23402834
56 Doisne JM, Becourt C, Amniai L, Duarte N, Le Luduec JB, Eberl G, Benlagha K. Skin and peripheral lymph node invariant NKT cells are mainly retinoic acid receptor-related orphan receptor γt+ and respond preferentially under inflammatory conditions. J Immunol 2009; 183(3): 2142–2149
https://doi.org/10.4049/jimmunol.0901059 pmid: 19587013
57 Gapin L. Development of invariant natural killer T cells. Curr Opin Immunol 2016; 39: 68–74
https://doi.org/10.1016/j.coi.2016.01.001 pmid: 26802287
58 Kim EY, Lynch L, Brennan PJ, Cohen NR, Brenner MB. The transcriptional programs of iNKT cells. Semin Immunol 2015; 27(1): 26–32
https://doi.org/10.1016/j.smim.2015.02.005 pmid: 25841627
59 Scanlon ST, Thomas SY, Ferreira CM, Bai L, Krausz T, Savage PB, Bendelac A. Airborne lipid antigens mobilize resident intravascular NKT cells to induce allergic airway inflammation. J Exp Med 2011; 208(10): 2113–2124
https://doi.org/10.1084/jem.20110522 pmid: 21930768
60 Terashima A, Watarai H, Inoue S, Sekine E, Nakagawa R, Hase K, Iwamura C, Nakajima H, Nakayama T, Taniguchi M. A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J Exp Med 2008; 205(12): 2727–2733
https://doi.org/10.1084/jem.20080698 pmid: 19015310
61 Yoshiga Y, Goto D, Segawa S, Ohnishi Y, Matsumoto I, Ito S, Tsutsumi A, Taniguchi M, Sumida T. Invariant NKT cells produce IL-17 through IL-23-dependent and -independent pathways with potential modulation of Th17 response in collagen-induced arthritis. Int J Mol Med 2008; 22(3): 369–374
pmid: 18698497
62 Pichavant M, Goya S, Meyer EH, Johnston RA, Kim HY, Matangkasombut P, Zhu M, Iwakura Y, Savage PB, DeKruyff RH, Shore SA, Umetsu DT. Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17. J Exp Med 2008; 205(2): 385–393
https://doi.org/10.1084/jem.20071507 pmid: 18250191
63 Michel ML, Keller AC, Paget C, Fujio M, Trottein F, Savage PB, Wong CH, Schneider E, Dy M, Leite-de-Moraes MC. Identification of an IL-17-producing NK1.1(neg) iNKT cell population involved in airway neutrophilia. J Exp Med 2007; 204(5): 995–1001
https://doi.org/10.1084/jem.20061551 pmid: 17470641
64 Sag D, Krause P, Hedrick CC, Kronenberg M, Wingender G. IL-10-producing NKT10 cells are a distinct regulatory invariant NKT cell subset. J Clin Invest 2014; 124(9): 3725–3740
https://doi.org/10.1172/JCI72308 pmid: 25061873
65 Dashtsoodol N, Shigeura T, Aihara M, Ozawa R, Kojo S, Harada M, Endo TA, Watanabe T, Ohara O, Taniguchi M. Alternative pathway for the development of Vα14+ NKT cells directly from CD4−CD8− thymocytes that bypasses the CD4+CD8+ stage. Nat Immunol 2017; 18(3): 274–282
https://doi.org/10.1038/ni.3668 pmid: 28135253
66 Lee PT, Benlagha K, Teyton L, Bendelac A. Distinct functional lineages of human Vα24 natural killer T cells. J Exp Med 2002; 195(5): 637–641
https://doi.org/10.1084/jem.20011908 pmid: 11877486
67 Doherty G, Golden-Mason L. NKT cells from normal and tumor-bearing human livers are phenotypically and functionally distinct from murine NKT cells. J Immunol 2003; 171(10): 1775–1779 PMID:12902477
https://doi.org/10.4049/jimmunol.171.10.5631
68 Brennan PJ, Brigl M, Brenner MB. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol 2013; 13(2): 101–117
https://doi.org/10.1038/nri3369 pmid: 23334244
69 O’Reilly V, Zeng SG, Bricard G, Atzberger A, Hogan AE, Jackson J, Feighery C, Porcelli SA, Doherty DG. Distinct and overlapping effector functions of expanded human CD4+, CD8+ and CD4−CD8− invariant natural killer T cells. PLoS One 2011; 6(12): e28648
https://doi.org/10.1371/journal.pone.0028648 pmid: 22174854
70 Bandyopadhyay K, Marrero I, Kumar V. NKT cell subsets as key participants in liver physiology and pathology. Cell Mol Immunol 2016; 13(3): 337–346
https://doi.org/10.1038/cmi.2015.115 pmid: 26972772
71 Gao B. Basic liver immunology. Cell Mol Immunol 2016; 13(3): 265–266
https://doi.org/10.1038/cmi.2016.09 pmid: 27041634
72 Lan P, Fan Y, Zhao Y, Lou X, Monsour HP, Zhang X, Choi Y, Dou Y, Ishii N, Ghobrial RM, Xiao X, Li XC. TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury. J Clin Invest 2017; 127(6): 2222–2234
https://doi.org/10.1172/JCI91075 pmid: 28436935
73 Fahey S, Dempsey E, Long A. The role of chemokines in acute and chronic hepatitis C infection. Cell Mol Immunol 2014; 11(1): 25–40
https://doi.org/10.1038/cmi.2013.37 pmid: 23954947
74 Wang X, Dong A, Xiao J, Zhou X, Mi H, Xu H, Zhang J, Wang B. Overcoming HBV immune tolerance to eliminate HBsAg-positive hepatocytes via pre-administration of GM-CSF as a novel adjuvant for a hepatitis B vaccine in HBV transgenic mice. Cell Mol Immunol 2016; 13(6): 850–861
https://doi.org/10.1038/cmi.2015.64 pmid: 26166767
75 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
pmid: 27238466
76 Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 2006; 1(1): 23–61
https://doi.org/10.1146/annurev.pathol.1.110304.100230 pmid: 18039107
77 Huang LM, Lu CY, Chen DS. Hepatitis B virus infection, its sequelae, and prevention by vaccination. Curr Opin Immunol 2011; 23(2): 237–243
https://doi.org/10.1016/j.coi.2010.12.013 pmid: 21257300
78 Guy CS, Mulrooney-Cousins PM, Churchill ND, Michalak TI. Intrahepatic expression of genes affiliated with innate and adaptive immune responses immediately after invasion and during acute infection with woodchuck hepadnavirus. J Virol 2008; 82(17): 8579–8591
https://doi.org/10.1128/JVI.01022-08 pmid: 18596101
79 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(7): 974–982
https://doi.org/10.1136/gut.2008.163600 pmid: 19201769
80 Webster GJ, Reignat S, Maini MK, Whalley SA, Ogg GS, King A, Brown D, Amlot PL, Williams R, Vergani D, Dusheiko GM, Bertoletti A. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 2000; 32(5): 1117–1124
https://doi.org/10.1053/jhep.2000.19324 pmid: 11050064
81 Jiang X, Zhang M, Lai Q, Huang X, Li Y, Sun J, Abbott WG, Ma S, Hou J. Restored circulating invariant NKT cells are associated with viral control in patients with chronic hepatitis B. PLoS One 2011; 6(12): e28871
https://doi.org/10.1371/journal.pone.0028871 pmid: 22194934
82 de Lalla C, Galli G, Aldrighetti L, Romeo R, Mariani M, Monno A, Nuti S, Colombo M, Callea F, Porcelli SA, Panina-Bordignon P, Abrignani S, Casorati G, Dellabona P. Production of profibrotic cytokines by invariant NKT cells characterizes cirrhosis progression in chronic viral hepatitis. J Immunol 2004; 173(2): 1417–1425
https://doi.org/10.4049/jimmunol.173.2.1417 pmid: 15240738
83 Zhu H, Zhang Y, Liu H, Zhang Y, Kang Y, Mao R, Yang F, Zhou D, Zhang J. Preserved function of circulating invariant natural killer T cells in patients with chronic hepatitis B virus infection. Medicine (Baltimore) 2015; 94(24): e961
https://doi.org/10.1097/MD.0000000000000961 pmid: 26091463
84 Ito H, Ando K, Ishikawa T, Nakayama T, Taniguchi M, Saito K, Imawari M, Moriwaki H, Yokochi T, Kakumu S, Seishima M. Role of Vα14+ NKT cells in the development of hepatitis B virus-specific CTL: activation of Vα14+ NKT cells promotes the breakage of CTL tolerance. Int Immunol 2008; 20(7): 869–879
https://doi.org/10.1093/intimm/dxn046 pmid: 18487227
85 Kakimi K, Guidotti LG, Koezuka Y, Chisari FV. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J Exp Med 2000; 192(7): 921–930
https://doi.org/10.1084/jem.192.7.921 pmid: 11015434
86 Zeissig S, Murata K, Sweet L, Publicover J, Hu Z, Kaser A, Bosse E, Iqbal J, Hussain MM, Balschun K, Röcken C, Arlt A, Günther R, Hampe J, Schreiber S, Baron JL, Moody DB, Liang TJ, Blumberg RS. Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity. Nat Med 2012; 18(7): 1060–1068
https://doi.org/10.1038/nm.2811 pmid: 22706385
87 Woltman AM, Ter Borg MJ, Binda RS, Sprengers D, von Blomberg BM, Scheper RJ, Hayashi K, Nishi N, Boonstra A, van der Molen R, Janssen HL. α-Galactosylceramide in chronic hepatitis B infection: results from a randomized placebo-controlled Phase I/II trial. Antivir Ther 2009; 14(6): 809–818
https://doi.org/10.3851/IMP1295 pmid: 19812443
88 van der Vliet HJ, Molling JW, von Blomberg BM, Kölgen W, Stam AG, de Gruijl TD, Mulder CJ, Janssen HL, Nishi N, van den Eertwegh AJ, Scheper RJ, van Nieuwkerk CJ. Circulating Vα24+Vβ11+ NKT cell numbers and dendritic cell CD1d expression in hepatitis C virus infected patients. Clin Immunol 2005; 114(2): 183–189
https://doi.org/10.1016/j.clim.2004.10.001 pmid: 15639652
89 Inoue M, Kanto T, Miyatake H, Itose I, Miyazaki M, Yakushijin T, Sakakibara M, Kuzushita N, Hiramatsu N, Takehara T, Kasahara A, Hayashi N. Enhanced ability of peripheral invariant natural killer T cells to produce IL-13 in chronic hepatitis C virus infection. J Hepatol 2006; 45(2): 190–196
https://doi.org/10.1016/j.jhep.2006.01.034 pmid: 16580086
90 Deignan T, Curry MP, Doherty DG, Golden-Mason L, Volkov Y, Norris S, Nolan N, Traynor O, McEntee G, Hegarty JE, O’Farrelly C. Decrease in hepatic CD56+ T cells and Vα24+ natural killer T cells in chronic hepatitis C viral infection. J Hepatol 2002; 37(1): 101–108
https://doi.org/10.1016/S0168-8278(02)00072-7 pmid: 12076868
91 Lucas M, Gadola S, Meier U, Young NT, Harcourt G, Karadimitris A, Coumi N, Brown D, Dusheiko G, Cerundolo V, Klenerman P. Frequency and phenotype of circulating Vα24/Vβ11 double-positive natural killer T cells during hepatitis C virus infection. J Virol 2003; 77(3): 2251–2257
https://doi.org/10.1128/JVI.77.3.2251-2257.2003 pmid: 12525661
92 Werner JM, Heller T, Gordon AM, Sheets A, Sherker AH, Kessler E, Bean KS, Stevens M, Schmitt J, Rehermann B. Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection. Hepatology 2013; 58(5): 1621–1631
https://doi.org/10.1002/hep.26353 pmid: 23463364
93 Miyaki E, Hiraga N, Imamura M, Uchida T, Kan H, Tsuge M, Abe-Chayama H, Hayes CN, Makokha GN, Serikawa M, Aikata H, Ochi H, Ishida Y, Tateno C, Ohdan H, Chayama K. Interferon α treatment stimulates interferon γ expression in type I NKT cells and enhances their antiviral effect against hepatitis C virus. PLoS One 2017; 12(3): e0172412
https://doi.org/10.1371/journal.pone.0172412 pmid: 28253324
94 Exley MA, He Q, Cheng O, Wang RJ, Cheney CP, Balk SP, Koziel MJ. Cutting edge: compartmentalization of Th1-like noninvariant CD1d-reactive T cells in hepatitis C virus-infected liver. J Immunol 2002; 168(4): 1519–1523
https://doi.org/10.4049/jimmunol.168.4.1519 pmid: 11823474
95 Durante-Mangoni E, Wang R, Shaulov A, He Q, Nasser I, Afdhal N, Koziel MJ, Exley MA. Hepatic CD1d expression in hepatitis C virus infection and recognition by resident proinflammatory CD1d-reactive T cells. J Immunol 2004; 173(3): 2159–2166
https://doi.org/10.4049/jimmunol.173.3.2159 pmid: 15265953
96 Li M, Zhou ZH, Sun XH, Zhang X, Zhu XJ, Jin SG, Jiang Y, Gao YT, Li CZ, Gao YQ. The dynamic changes of circulating invariant natural killer T cells during chronic hepatitis B virus infection. Hepatol Int 2016; 10(4): 594–601
https://doi.org/10.1007/s12072-015-9650-0 pmid: 26924524
97 Wang H, Feng D, Park O, Yin S, Gao B. Invariant NKT cell activation induces neutrophil accumulation and hepatitis: opposite regulation by IL-4 and IFN-g. Hepatology 2013; 58(4): 1474–1485
https://doi.org/10.1002/hep.26471 pmid: 23686838
98 Hirschfield GM, Heathcote EJ, Gershwin ME. Pathogenesis of cholestatic liver disease and therapeutic approaches. Gastroenterology 2010; 139(5): 1481–1496
https://doi.org/10.1053/j.gastro.2010.09.004 pmid: 20849855
99 Liaskou E, Hirschfield GM, Gershwin ME. Mechanisms of tissue injury in autoimmune liver diseases. Semin Immunopathol 2014; 36(5): 553–568
https://doi.org/10.1007/s00281-014-0439-3 pmid: 25082647
100 Kita H, Naidenko OV, Kronenberg M, Ansari AA, Rogers P, He XS, Koning F, Mikayama T, Van De Water J, Coppel RL, Kaplan M, Gershwin ME. Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology 2002; 123(4): 1031–1043
https://doi.org/10.1053/gast.2002.36020 pmid: 12360465
101 Tsuneyama K, Yasoshima M, Harada K, Hiramatsu K, Gershwin ME, Nakanuma Y. Increased CD1d expression on small bile duct epithelium and epithelioid granuloma in livers in primary biliary cirrhosis. Hepatology 1998; 28(3): 620–623
https://doi.org/10.1002/hep.510280303 pmid: 9731549
102 Sebode M, Schramm C. Natural killer T cells: novel players in biliary disease? Hepatology 2015; 62(4): 999–1000
https://doi.org/10.1002/hep.27862 pmid: 25914184
103 Chuang YH, Lian ZX, Yang GX, Shu SA, Moritoki Y, Ridgway WM, Ansari AA, Kronenberg M, Flavell RA, Gao B, Gershwin ME. Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology 2008; 47(2): 571–580
https://doi.org/10.1002/hep.22052 pmid: 18098320
104 Olszak T, Neves JF, Dowds CM, Baker K, Glickman J, Davidson NO, Lin CS, Jobin C, Brand S, Sotlar K, Wada K, Katayama K, Nakajima A, Mizuguchi H, Kawasaki K, Nagata K, Müller W, Snapper SB, Schreiber S, Kaser A, Zeissig S, Blumberg RS. Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature 2014; 509(7501): 497–502
https://doi.org/10.1038/nature13150 pmid: 24717441
105 Wu SJ, Yang YH, Tsuneyama K, Leung PSC, Illarionov P, Gershwin ME, Chuang YH. Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis. Hepatology 2011; 53(3): 915–925
https://doi.org/10.1002/hep.24113 pmid: 21374662
106 Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, Pendem K, Teyton L, Hart J, Ridgway WM, Wicker LS, Gershwin ME, Bendelac A. Liver autoimmunity triggered by microbial activation of natural killer T cells. Cell Host Microbe 2008; 3(5): 304–315
https://doi.org/10.1016/j.chom.2008.03.009 pmid: 18474357
107 O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Am J Gastroenterol 2010; 105(1): 14–32, quiz 33
https://doi.org/10.1038/ajg.2009.593 pmid: 19904248
108 Beier JI, McClain CJ. Mechanisms and cell signaling in alcoholic liver disease. Biol Chem 2010; 391(11): 1249–1264
https://doi.org/10.1515/bc.2010.137 pmid: 20868231
109 Kono H, Rusyn I, Yin M, Gäbele E, Yamashina S, Dikalova A, Kadiiska MB, Connor HD, Mason RP, Segal BH, Bradford BU, Holland SM, Thurman RG. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest 2000; 106(7): 867–872
https://doi.org/10.1172/JCI9020 pmid: 11018074
110 Laso FJ, Vaquero JM, Almeida J, Marcos M, Orfao A. Chronic alcohol consumption is associated with changes in the distribution, immunophenotype, and the inflammatory cytokine secretion profile of circulating dendritic cells. Alcohol Clin Exp Res 2007; 31(5): 846–854
https://doi.org/10.1111/j.1530-0277.2007.00377.x pmid: 17386065
111 Lau AH, Abe M, Thomson AW. Ethanol affects the generation, cosignaling molecule expression, and function of plasmacytoid and myeloid dendritic cell subsets in vitro and in vivo. J Leukoc Biol 2006; 79(5): 941–953
https://doi.org/10.1189/jlb.0905517 pmid: 16478920
112 Stadlbauer V, Mookerjee RP, Wright GA, Davies NA, Jürgens G, Hallström S, Jalan R. Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol 2009; 296(1): G15–G22
https://doi.org/10.1152/ajpgi.90512.2008 pmid: 19033535
113 Zhang H, Meadows GG. Chronic alcohol consumption in mice increases the proportion of peripheral memory T cells by homeostatic proliferation. J Leukoc Biol 2005; 78(5): 1070–1080
https://doi.org/10.1189/jlb.0605317 pmid: 16260584
114 Lemmers A, Moreno C, Gustot T, Maréchal R, Degré D, Demetter P, de Nadai P, Geerts A, Quertinmont E, Vercruysse V, Le Moine O, Devière J. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology 2009; 49(2): 646–657
https://doi.org/10.1002/hep.22680 pmid: 19177575
115 Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G. Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-α during alcohol consumption. Gastroenterology 2004; 126(5): 1387–1399
https://doi.org/10.1053/j.gastro.2004.01.022 pmid: 15131799
116 Mathews S, Feng D, Maricic I, Ju C, Kumar V, Gao B. Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration. Cell Mol Immunol 2016; 13(2): 206–216
https://doi.org/10.1038/cmi.2015.06 pmid: 25661730
117 Maricic I, Sheng H, Marrero I, Seki E, Kisseleva T, Chaturvedi S, Molle N, Mathews SA, Gao B, Kumar V. Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice. Hepatology 2015; 61(4): 1357–1369
https://doi.org/10.1002/hep.27632 pmid: 25477000
118 Buschard K, Hansen AK, Jensen K, Lindenbergh-Kortleve DJ, de Ruiter LF, Krohn TC, Hufeldt MR, Vogensen FK, Aasted B, Osterbye T, Roep BO, de Haar C, Nieuwenhuis EE. Alcohol facilitates CD1d loading, subsequent activation of NKT cells, and reduces the incidence of diabetes in NOD mice. PLoS One 2011; 6(4): e17931
https://doi.org/10.1371/journal.pone.0017931 pmid: 21483778
119 Cui K, Yan G, Xu C, Chen Y, Wang J, Zhou R, Bai L, Lian Z, Wei H, Sun R, Tian Z. Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1β in mice. J Hepatol 2015; 62(6): 1311–1318
https://doi.org/10.1016/j.jhep.2014.12.027 pmid: 25582105
120 Bertola A, Park O, Gao B. Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: a critical role for E-selectin. Hepatology 2013; 58(5): 1814–1823
https://doi.org/10.1002/hep.26419 pmid: 23532958
121 Jeong D, Ahn S, Oh S J, Ahn J Y, Lee S H, Chung D H. GM-CSF and IL-4 produced by NKT cells inversely regulate IL-1β production by macrophages. J Immunol 2014; 192
122 Mikolasevic I, Milic S, Turk Wensveen T, Grgic I, Jakopcic I, Stimac D, Wensveen F, Orlic L. Nonalcoholic fatty liver disease — a multisystem disease? World J Gastroenterol 2016; 22(43): 9488–9505
https://doi.org/10.3748/wjg.v22.i43.9488 pmid: 27920470
123 Hart KM, Fabre T, Sciurba JC, Gieseck RL 3rd, Borthwick LA, Vannella KM, Acciani TH, de Queiroz Prado R, Thompson RW, White S, Soucy G, Bilodeau M, Ramalingam TR, Arron JR, Shoukry NH, Wynn TA. Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-β. Sci Transl Med 2017; 9(396): eaal3694
https://doi.org/10.1126/scitranslmed.aal3694 pmid: 28659437
124 Parekh S, Anania FA. Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease. Gastroenterology 2007; 132(6): 2191–2207
https://doi.org/10.1053/j.gastro.2007.03.055 pmid: 17498512
125 Bhattacharjee J, Kirby M, Softic S, Miles L, Salazar-Gonzalez RM, Shivakumar P, Kohli R. Hepatic natural killer T-cell and CD8+ T-cell signatures in mice with nonalcoholic steatohepatitis. Hepatol Commun 2017; 1(4): 299–310
https://doi.org/10.1002/hep4.1041 pmid: 29152605
126 Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482(7384): 179–185
https://doi.org/10.1038/nature10809 pmid: 22297845
127 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444(7121): 860–867
https://doi.org/10.1038/nature05485 pmid: 17167474
128 Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2010; 7(4): 195–203
https://doi.org/10.1038/nrgastro.2010.21 pmid: 20195271
129 Guebre-Xabier M, Yang S, Lin HZ, Schwenk R, Krzych U, Diehl AM. Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage. Hepatology 2000; 31(3): 633–640
https://doi.org/10.1002/hep.510310313 pmid: 10706553
130 Li Z, Lin H, Yang S, Diehl AM. Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system. Gastroenterology 2002; 123(4): 1304–1310
https://doi.org/10.1053/gast.2002.35997 pmid: 12360490
131 Yang L, Jhaveri R, Huang J, Qi Y, Diehl AM. Endoplasmic reticulum stress, hepatocyte CD1d and NKT cell abnormalities in murine fatty livers. Lab Invest 2007; 87(9): 927–937
https://doi.org/10.1038/labinvest.3700603 pmid: 17607300
132 Tang ZH, Liang S, Potter J, Jiang X, Mao HQ, Li Z. Tim-3/galectin-9 regulate the homeostasis of hepatic NKT cells in a murine model of nonalcoholic fatty liver disease. J Immunol 2013; 190(4): 1788–1796
https://doi.org/10.4049/jimmunol.1202814 pmid: 23296703
133 Li Z, Soloski MJ, Diehl AM. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology 2005; 42(4): 880–885
https://doi.org/10.1002/hep.20826 pmid: 16175608
134 Ma X, Hua J, Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol 2008; 49(5): 821–830
https://doi.org/10.1016/j.jhep.2008.05.025 pmid: 18674841
135 Kremer M, Hines IN, Milton RJ, Wheeler MD. Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis. Hepatology 2006; 44(1): 216–227
https://doi.org/10.1002/hep.21221 pmid: 16799967
136 Kremer M, Thomas E, Milton RJ, Perry AW, van Rooijen N, Wheeler MD, Zacks S, Fried M, Rippe RA, Hines IN. Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis. Hepatology 2010; 51(1): 130–141
https://doi.org/10.1002/hep.23292 pmid: 20034047
137 Li Z, Oben JA, Yang S, Lin H, Stafford EA, Soloski MJ, Thomas SA, Diehl AM. Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis. Hepatology 2004; 40(2): 434–441
https://doi.org/10.1002/hep.20320 pmid: 15368448
138 Miyazaki Y, Iwabuchi K, Iwata D, Miyazaki A, Kon Y, Niino M, Kikuchi S, Yanagawa Y, Kaer LV, Sasaki H, Onoé K. Effect of high fat diet on NKT cell function and NKT cell-mediated regulation of Th1 responses. Scand J Immunol 2008; 67(3): 230–237
https://doi.org/10.1111/j.1365-3083.2007.02062.x pmid: 18226013
139 Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, Balk SP, O’Shea D, O’Farrelly C, Exley MA. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 2012; 37(3): 574–587
https://doi.org/10.1016/j.immuni.2012.06.016 pmid: 22981538
140 Elinav E, Pappo O, Sklair-Levy M, Margalit M, Shibolet O, Gomori M, Alper R, Thalenfeld B, Engelhardt D, Rabbani E, Ilan Y. Adoptive transfer of regulatory NKT lymphocytes ameliorates non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice and is associated with intrahepatic CD8 trapping. J Pathol 2006; 209(1): 121–128
https://doi.org/10.1002/path.1950 pmid: 16482497
141 Wu L, Parekh VV, Gabriel CL, Bracy DP, Marks-Shulman PA, Tamboli RA, Kim S, Mendez-Fernandez YV, Besra GS, Lomenick JP, Williams B, Wasserman DH, Van Kaer L. Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc Natl Acad Sci USA 2012; 109(19): E1143–E1152
https://doi.org/10.1073/pnas.1200498109 pmid: 22493234
142 Satoh M, Andoh Y, Clingan CS, Ogura H, Fujii S, Eshima K, Nakayama T, Taniguchi M, Hirata N, Ishimori N, Tsutsui H, Onoé K, Iwabuchi K. Type II NKT cells stimulate diet-induced obesity by mediating adipose tissue inflammation, steatohepatitis and insulin resistance. PLoS One 2012; 7(2): e30568
https://doi.org/10.1371/journal.pone.0030568 pmid: 22383967
143 Syn WK, Agboola KM, Swiderska M, Michelotti GA, Liaskou E, Pang H, Xie G, Philips G, Chan IS, Karaca GF, Pereira TA, Chen Y, Mi Z, Kuo PC, Choi SS, Guy CD, Abdelmalek MF, Diehl AM. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 2012; 61(9): 1323–1329
https://doi.org/10.1136/gutjnl-2011-301857 pmid: 22427237
144 Syn WK, Oo YH, Pereira TA, Karaca GF, Jung Y, Omenetti A, Witek RP, Choi SS, Guy CD, Fearing CM, Teaberry V, Pereira FE, Adams DH, Diehl AM. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 2010; 51(6): 1998–2007
https://doi.org/10.1002/hep.23599 pmid: 20512988
145 Wolf MJ, Adili A, Piotrowitz K, Abdullah Z, Boege Y, Stemmer K, Ringelhan M, Simonavicius N, Egger M, Wohlleber D, Lorentzen A, Einer C, Schulz S, Clavel T, Protzer U, Thiele C, Zischka H, Moch H, Tschöp M, Tumanov AV, Haller D, Unger K, Karin M, Kopf M, Knolle P, Weber A, Heikenwalder M. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 2014; 26(4): 549–564
https://doi.org/10.1016/j.ccell.2014.09.003 pmid: 25314080
146 Tajiri K, Shimizu Y, Tsuneyama K, Sugiyama T. Role of liver-infiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2009; 21(6): 673–680
https://doi.org/10.1097/MEG.0b013e32831bc3d6 pmid: 19318971
147 Adler M, Taylor S, Okebugwu K, Yee H, Fielding C, Fielding G, Poles M. Intrahepatic natural killer T cell populations are increased in human hepatic steatosis. World J Gastroenterol 2011; 17(13): 1725–1731
https://doi.org/10.3748/wjg.v17.i13.1725 pmid: 21483633
148 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61(2): 69–90
https://doi.org/10.3322/caac.20107 pmid: 21296855
149 Li S, Ye L, Yu X, Xu B, Li K, Zhu X, Liu H, Wu X, Kong L. Hepatitis C virus NS4B induces unfolded protein response and endoplasmic reticulum overload response-dependent NF-κB activation. Virology 2009; 391(2): 257–264
https://doi.org/10.1016/j.virol.2009.06.039 pmid: 19628242
150 Hernaez R, El-Serag HB. Hepatocellular carcinoma surveillance: the road ahead. Hepatology 2017; 65(3): 771–773
https://doi.org/10.1002/hep.28983 pmid: 27943335
151 Miyagi T, Takehara T, Tatsumi T, Kanto T, Suzuki T, Jinushi M, Sugimoto Y, Sasaki Y, Hori M, Hayashi N. CD1d-mediated stimulation of natural killer T cells selectively activates hepatic natural killer cells to eliminate experimentally disseminated hepatoma cells in murine liver. Int J Cancer 2003; 106(1): 81–89
https://doi.org/10.1002/ijc.11163 pmid: 12794761
152 Margalit M, Shibolet O, Klein A, Elinav E, Alper R, Thalenfeld B, Engelhardt D, Rabbani E, Ilan Y. Suppression of hepatocellular carcinoma by transplantation of ex-vivo immune-modulated NKT lymphocytes. Int J Cancer 2005; 115(3): 443–449
https://doi.org/10.1002/ijc.20889 pmid: 15688366
153 Motohashi S, Nagato K, Kunii N, Yamamoto H, Yamasaki K, Okita K, Hanaoka H, Shimizu N, Suzuki M, Yoshino I, Taniguchi M, Fujisawa T, Nakayama T. A phase I-II study of α-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J Immunol 2009; 182(4): 2492–2501
https://doi.org/10.4049/jimmunol.0800126 pmid: 19201905
154 Ishikawa A, Motohashi S, Ishikawa E, Fuchida H, Higashino K, Otsuji M, Iizasa T, Nakayama T, Taniguchi M, Fujisawa T. A phase I study of α-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res 2005; 11(5): 1910–1917
https://doi.org/10.1158/1078-0432.CCR-04-1453 pmid: 15756017
155 Yamasaki K, Horiguchi S, Kurosaki M, Kunii N, Nagato K, Hanaoka H, Shimizu N, Ueno N, Yamamoto S, Taniguchi M, Motohashi S, Nakayama T, Okamoto Y. Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin Immunol 2011; 138(3): 255–265
https://doi.org/10.1016/j.clim.2010.11.014 pmid: 21185787
156 Uchida T, Horiguchi S, Tanaka Y, Yamamoto H, Kunii N, Motohashi S, Taniguchi M, Nakayama T, Okamoto Y. Phase I study of α-galactosylceramide-pulsed antigen presenting cells administration to the nasal submucosa in unresectable or recurrent head and neck cancer. Cancer Immunol Immunother 2008; 57(3): 337–345
https://doi.org/10.1007/s00262-007-0373-5 pmid: 17690880
157 Giaccone G, Punt CJ, Ando Y, Ruijter R, Nishi N, Peters M, von Blomberg BM, Scheper RJ, van der Vliet HJ, van den Eertwegh AJ, Roelvink M, Beijnen J, Zwierzina H, Pinedo HM. A phase I study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 2002; 8(12): 3702–3709
pmid: 12473579
158 Heczey A, Liu D, Tian G, Courtney AN, Wei J, Marinova E, Gao X, Guo L, Yvon E, Hicks J, Liu H, Dotti G, Metelitsa LS. Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy. Blood 2014; 124(18): 2824–2833
https://doi.org/10.1182/blood-2013-11-541235 pmid: 25049283
159 Tian G, Courtney AN, Jena B, Heczey A, Liu D, Marinova E, Guo L, Xu X, Torikai H, Mo Q, Dotti G, Cooper LJ, Metelitsa LS. CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo. J Clin Invest 2016; 126(6): 2341–2355
https://doi.org/10.1172/JCI83476 pmid: 27183388
160 Dhodapkar KM, Cirignano B, Chamian F, Zagzag D, Miller DC, Finlay JL, Steinman RM. Invariant natural killer T cells are preserved in patients with glioma and exhibit antitumor lytic activity following dendritic cell-mediated expansion. Int J Cancer 2004; 109(6): 893–899
https://doi.org/10.1002/ijc.20050 pmid: 15027123
161 Motohashi S, Kobayashi S, Ito T, Magara KK, Mikuni O, Kamada N, Iizasa T, Nakayama T, Fujisawa T, Taniguchi M. Preserved IFN-α production of circulating Vα24 NKT cells in primary lung cancer patients. Int J Cancer 2002; 102(2): 159–165
https://doi.org/10.1002/ijc.10678 pmid: 12385012
162 Motohashi S, Okamoto Y, Yoshino I, Nakayama T. Anti-tumor immune responses induced by iNKT cell-based immunotherapy for lung cancer and head and neck cancer. Clin Immunol 2011; 140(2): 167–176
https://doi.org/10.1016/j.clim.2011.01.009 pmid: 21349771
163 Xiao YS, Gao Q, Xu XN, Li YW, Ju MJ, Cai MY, Dai CX, Hu J, Qiu SJ, Zhou J, Fan J. Combination of intratumoral invariant natural killer T cells and interferon-γ is associated with prognosis of hepatocellular carcinoma after curative resection. PLoS One 2013; 8(8): e70345
https://doi.org/10.1371/journal.pone.0070345 pmid: 23940564
164 Bricard G, Cesson V, Devevre E, Bouzourene H, Barbey C, Rufer N, Im JS, Alves PM, Martinet O, Halkic N, Cerottini JC, Romero P, Porcelli SA, Macdonald HR, Speiser DE. Enrichment of human CD4+ Vα24/Vβ11 invariant NKT cells in intrahepatic malignant tumors. J Immunol 2009; 182(8): 5140–5151
https://doi.org/10.4049/jimmunol.0711086 pmid: 19342695
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[5] Zhen He,Cheng Hu,Weiping Jia. miRNAs in non-alcoholic fatty liver disease[J]. Front. Med., 2016, 10(4): 389-396.
[6] Xinsen Xu,Yanyan Zhou,Runchen Miao,Wei Chen,Kai Qu,Qing Pang,Chang Liu. Transcriptional modules related to hepatocellular carcinoma survival: coexpression network analysis[J]. Front. Med., 2016, 10(2): 183-190.
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[8] Felice Ho-Ching Tsang,Sandy Leung-Kuen Au,Lai Wei,Dorothy Ngo-Yin Fan,Joyce Man-Fong Lee,Carmen Chak-Lui Wong,Irene Oi-Lin Ng,Chun-Ming Wong. MicroRNA-142-3p and microRNA-142-5p are downregulated in hepatocellular carcinoma and exhibit synergistic effects on cell motility[J]. Front. Med., 2015, 9(3): 331-343.
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[10] Farhad Sahebjam,John M. Vierling. Autoimmune hepatitis[J]. Front. Med., 2015, 9(2): 187-219.
[11] Guanghua Rong,Wenlin Bai,Zheng Dong,Chunping Wang,Yinying Lu,Zhen Zeng,Jianhui Qu,Min Lou,Hong Wang,Xudong Gao,Xiujuan Chang,Linjing An,Yan Chen,Yongping Yang. Cryotherapy for cirrhosis-based hepatocellular carcinoma: a single center experience from 1595 treated cases[J]. Front. Med., 2015, 9(1): 63-71.
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