Skip to main content
SpringerLink
Log in

NKT cells in liver diseases

  • Review
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Makino Y, Kanno R, Ito T, Higashino K, Taniguchi M. Predominant expression of invariant Vα14+ TCRa chain in NK1.1+ T cell populations. Int Immunol 1995; 7(7): 1157–1161

    Article  PubMed  CAS  Google Scholar 

  2. Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong ST, Brenner MB. Recognition of a lipid antigen by CD1-restricted aβ+ T cells. Nature 1994; 372(6507): 691–694

    Article  PubMed  CAS  Google Scholar 

  3. Godfrey DI, Hammond KJL, Poulton LD, Smyth MJ, Baxter AG. NKT cells: facts, functions and fallacies. Immunol Today 2000; 21 (11): 573–583

    Article  PubMed  CAS  Google Scholar 

  4. Dascher CC, Brenner MB. Evolutionary constraints on CD1 structure: insights from comparative genomic analysis. Trends Immunol 2003; 24(8): 412–418

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  6. Brossay L, Chioda M, Burdin N, Koezuka Y, Casorati G, Dellabona P, Kronenberg M. CD1d-mediated recognition of an a-galactosylceramide by natural killer T cells is highly conserved through mammalian evolution. J Exp Med 1998; 188(8): 1521–1528

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Godfrey DI, Stankovic S, Baxter AG. Raising the NKT cell family. Nat Immunol 2010; 11(3): 197–206

    Article  PubMed  CAS  Google Scholar 

  8. Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007; 25(1): 297–336

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  12. Cerundolo V, Silk JD, Masri SH, Salio M. Harnessing invariant NKT cells in vaccination strategies. Nat Rev Immunol 2009; 9(1): 28–38

    Article  PubMed  CAS  Google Scholar 

  13. Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007; 25(1): 297–336

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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. a-Galactosylceramide induces early B-cell activation through IL-4 production by NKT cells. Cell Immunol 2000; 199 (1): 37–42

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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. CD1drestricted and TCR-mediated activation of Va14 NKT cells by glycosylceramides. Science 1997; 278(5343): 1626–1629

    Article  PubMed  CAS  Google Scholar 

  19. Godfrey DI, Stankovic S, Baxter AG. Raising the NKT cell family. Nat Immunol 2010; 11(3): 197–206

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  21. Savage PB, Teyton L, Bendelac A. Glycolipids for natural killer T cells. Chem Soc Rev 2006; 35(9): 771–779

    Article  PubMed  CAS  Google Scholar 

  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 a-galactosylceramide (KRN7000) and isoglobotrihexosylceramide (iGb3). Bioorg Med Chem Lett 2006; 16(8): 2195–2199

    Article  PubMed  CAS  Google Scholar 

  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 Va14Ja18 NKT lymphocyte antigen caused by β-D-glucosylceramide synthase deficiency. Proc Natl Acad Sci USA 2003; 100(4): 1849–1854

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Nagarajan NA, Kronenberg M. Invariant NKT cells amplify the innate immune response to lipopolysaccharide. J Immunol 2007; 178(5): 2706–2713

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  28. Godfrey DI, Rossjohn J. New ways to turn on NKT cells. J Exp Med 2011; 208(6): 1121–1125

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 a-galactosylceramides. Proc Natl Acad Sci USA 2005; 102(9): 3383–3388

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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 a-galactosylceramides on cytokine release by natural killer T cells. J Am Chem Soc 2004; 126(42): 13602–13603

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Chackerian A, Alt J, Perera V, Behar SM. Activation of NKT cells protects mice from tuberculosis. Infect Immun 2002; 70(11): 6302–6309

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Opasawatchai A, Matangkasombut P. iNKT cells and their potential lipid ligands during viral infection. Front Immunol 2015; 6: 378

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Google Scholar 

  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 longlived LFA-1-ICAM-1 interactions. J Exp Med 2011; 208(6): 1179–1188

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Slauenwhite D, Johnston B. Regulation of NKT cell localization in homeostasis and infection. Front Immunol 2015; 6: 255

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Constantinides MG, Bendelac A. Transcriptional regulation of the NKT cell lineage. Curr Opin Immunol 2013; 25(2): 161–167

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  57. Gapin L. Development of invariant natural killer T cells. Curr Opin Immunol 2016; 39: 68–74

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kim EY, Lynch L, Brennan PJ, Cohen NR, Brenner MB. The transcriptional programs of iNKT cells. Semin Immunol 2015; 27 (1): 26–32

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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 Va14+ NKT cells directly from CD4–CD8–thymocytes that bypasses the CD4+CD8+ stage. Nat Immunol 2017; 18(3): 274–282

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Doherty G, Golden-Mason L. NKT cells from normal and tumorbearing human livers are phenotypically and functionally distinct from murine NKT cells. J Immunol 2003; 171(10): 1775–1779 PMID:12902477

    PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Gao B. Basic liver immunology. Cell Mol Immunol 2016; 13(3): 265–266

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  76. Guidotti LG, Chisari FV. Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 2006; 1(1): 23–61

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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 virusspecific CTL: activation of Vα14+ NKT cells promotes the breakage of CTL tolerance. Int Immunol 2008; 20(7): 869–879

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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. a-Galactosylceramide in chronic hepatitis B infection: results from a randomized placebo-controlled Phase I/II trial. Antivir Ther 2009; 14(6): 809–818

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 doublepositive natural killer T cells during hepatitis C virus infection. J Virol 2003; 77(3): 2251–2257

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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 a 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 CD1dreactive T cells. J Immunol 2004; 173(3): 2159–2166

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Hirschfield GM, Heathcote EJ, Gershwin ME. Pathogenesis of cholestatic liver disease and therapeutic approaches. Gastroenterology 2010; 139(5): 1481–1496

    Article  PubMed  CAS  Google Scholar 

  99. Liaskou E, Hirschfield GM, Gershwin ME. Mechanisms of tissue injury in autoimmune liver diseases. Semin Immunopathol 2014; 36(5): 553–568

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  102. Sebode M, Schramm C. Natural killer T cells: novel players in biliary disease? Hepatology 2015; 62(4): 999–1000

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Am J Gastroenterol 2010; 105(1): 14–32, quiz 33

    Article  PubMed  Google Scholar 

  108. Beier JI, McClain CJ. Mechanisms and cell signaling in alcoholic liver disease. Biol Chem 2010; 391(11): 1249–1264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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-a during alcohol consumption. Gastroenterology 2004; 126(5): 1387–1399

    Article  PubMed  CAS  Google Scholar 

  116. Mathews S, Feng D, Maricic I, Ju C, Kumar V, Gao B. Invariant natural killer T cells contribute to chronic-plus-binge ethanolmediated liver injury by promoting hepatic neutrophil infiltration. Cell Mol Immunol 2016; 13(2): 206–216

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  124. Parekh S, Anania FA. Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease. Gastroenterology 2007; 132(6): 2191–2207

    Article  PubMed  CAS  Google Scholar 

  125. Bhattacharjee J, Kirby M, Softic S, Miles L, Salazar-Gonzalez RM, Shivakumar P, Kohli R. Hepatic natural killer T-cell and CD8+ Tcell signatures in mice with nonalcoholic steatohepatitis. Hepatol Commun 2017; 1(4): 299–310

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444(7121): 860–867

    Article  PubMed  CAS  Google Scholar 

  128. Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2010; 7(4): 195–203

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  146. Tajiri K, Shimizu Y, Tsuneyama K, Sugiyama T. Role of liverinfiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2009; 21(6): 673–680

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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-kB activation. Virology 2009; 391(2): 257–264

    Article  PubMed  CAS  Google Scholar 

  150. Hernaez R, El-Serag HB. Hepatocellular carcinoma surveillance: the road ahead. Hepatology 2017; 65(3): 771–773

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 a-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

    Article  PubMed  CAS  Google Scholar 

  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 a-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res 2005; 11(5): 1910–1917

    Article  PubMed  CAS  Google Scholar 

  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 cellspecific immune responses in cancer tissues after NKT celltargeted adoptive immunotherapy. Clin Immunol 2011; 138(3): 255–265

    Article  PubMed  CAS  Google Scholar 

  156. Uchida T, Horiguchi S, Tanaka Y, Yamamoto H, Kunii N, Motohashi S, Taniguchi M, Nakayama T, Okamoto Y. Phase I study of a-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

    Article  PubMed  CAS  Google Scholar 

  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 a-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 2002; 8 (12): 3702–3709

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  161. Motohashi S, Kobayashi S, Ito T, Magara KK, Mikuni O, Kamada N, Iizasa T, Nakayama T, Fujisawa T, Taniguchi M. Preserved IFN-a production of circulating Vα24 NKT cells in primary lung cancer patients. Int J Cancer 2002; 102(2): 159–165

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Work in the authors’ laboratory was supported by National Natural Science Foundation of China (Nos. 91542203, 31470859, and 81771671), National Key R&D Program of China (No. 2017YFA0505300), the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA12030208), the Fundamental Research Funds for the Central Universities.

Author information

Authors and Affiliations

  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

    Shasha Zhu, Huimin Zhang & Li Bai

  2. Innovation Center for Cell Signaling Network, Hefei National Laboratory for Physical Sciences at Microscale, Hefei, 230027, China

    Shasha Zhu, Huimin Zhang & Li Bai

Authors
  1. Shasha Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huimin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Bai.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, S., Zhang, H. & Bai, L. NKT cells in liver diseases. Front. Med. 12, 249–261 (2018). https://doi.org/10.1007/s11684-018-0622-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-018-0622-3

Keywords

Search

Navigation