Seminars in Immunopathology

, 31:333 | Cite as

Microanatomy of the liver immune system

  • Eszter Nemeth
  • Alan W. Baird
  • Cliona O’Farrelly
Review

Abstract

The critical metabolic functions of the liver often eclipse any perception of its role as an immune organ. However, the liver as a mediator of systemic and local innate immunity and an important site of immune regulation is now an accepted concept. Complex repertoires of lymphoid and non-lymphoid cells are key to hepatic defense and immunoregulation. Hepatic cells of myeloid lineage include Kupffer cells and dendritic cells. Intrahepatic lymphocytes are distinct both in phenotype and function from their counterparts in any other organ and include both conventional (CD4+ and CD8+ αβ T cell receptor (TCR)+ T cells, B cells, natural killer (NK) cells) and nonconventional lymphoid cells (natural killer T (NKT) cells, γδTCR+ T cells, CD4− CD8− T cells). Many hepatic T cells express the TCR at an intermediate level and the great majority of them either coexpress NK cell markers (NKT cells) or they are apoptosing peripheral T cells. The percentage of activated (CD69+) and memory (CD45RBlow+) lymphocytes is much higher while naïve (CD62Lhigh) and resting T cells as well as B lymphocytes are underrepresented in the liver. The discovery of major populations of lymphoid cells in the liver that differ phenotypically, functionally and even perhaps developmentally from populations in other regions has been key to the evolving perception of the liver as a regulatory lymphoid organ. This chapter will focus on these populations and how they contribute to immune surveillance against malignant, infectious and autoimmune disease of the liver.

Keywords

Hepatic innate immunity Natural killer cells Natural killer receptors (NKR) Invariant NKT cells T regulatory cells 

Notes

Acknowledgments

We are grateful to the EU Marie Curie Programme, the Health Research Board of Ireland (HRB Translational Research Award TRA/2007/14), and Science Foundation Ireland (SFI Research Frontiers Programme 05/RFP/BIC0012) for financial support and to Dr. Ann Hopkins for her help with confocal microscopy.

References

  1. 1.
    Abel M, Sene D et al (2006) Intrahepatic virus-specific IL-10-producing CD8 T cells prevent liver damage during chronic hepatitis C virus infection. Hepatology 44(6):1607–1616PubMedCrossRefGoogle Scholar
  2. 2.
    Accapezzato D, Francavilla V et al (2004) Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection. J Clin Invest 113(7):963–972PubMedGoogle Scholar
  3. 3.
    Armbrust T, Batusic D et al (1997) Mast cells distribution in human liver disease and experimental rat liver fibrosis. Indications for mast cell participation in development of liver fibrosis. J Hepatol 26(5):1042–1054PubMedCrossRefGoogle Scholar
  4. 4.
    Balter M (2000) Malaria. Can WHO roll back malaria? Science 290(5491):430PubMedCrossRefGoogle Scholar
  5. 5.
    Befus D, Fujimaki H et al (1988) Mast cell polymorphisms. Present concepts, future directions. Dig Dis Sci 33(3 Suppl):16S–24SPubMedCrossRefGoogle Scholar
  6. 6.
    Bendelac A, Savage PB et al (2007) The biology of NKT cells. Annu Rev Immunol 25:297–336PubMedCrossRefGoogle Scholar
  7. 7.
    Berland R, Wortis HH (2002) Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol 20:253–300PubMedCrossRefGoogle Scholar
  8. 8.
    Bertolino P, Trescol-Biemont MC et al (1998) Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival. Eur J Immunol 28(1):221–236PubMedCrossRefGoogle Scholar
  9. 9.
    Bettelli E, Korn T et al (2007) Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 19(6):652–657PubMedCrossRefGoogle Scholar
  10. 10.
    Bilzer M, Roggel F et al (2006) Role of Kupffer cells in host defense and liver disease. Liver Int 26(10):1175–1186PubMedCrossRefGoogle Scholar
  11. 11.
    Blom KG, Qazi MR et al (2009) Isolation of murine intrahepatic immune cells employing a modified procedure for mechanical disruption and functional characterization of the B, T and natural killer T cells obtained. Clin Exp Immunol 155(2):320–329PubMedCrossRefGoogle Scholar
  12. 12.
    Bochtler P, Riedl P et al (2008) Local accumulation and activation of regulatory Foxp3(+) CD4 T(R) cells accompanies the appearance of activated CD8 T cells in the liver. Hepatology 48:1954–1963PubMedCrossRefGoogle Scholar
  13. 13.
    Born WK, Reardon CL et al (2006) The function of gammadelta T cells in innate immunity. Curr Opin Immunol 18(1):31–38PubMedCrossRefGoogle Scholar
  14. 14.
    Braet F, de Zanger R et al (2001) A comparative atomic force microscopy study on living skin fibroblasts and liver endothelial cells. J Electron Microsc (Tokyo) 50(4):283–290CrossRefGoogle Scholar
  15. 15.
    Brandes M, Willimann K et al (2005) Professional antigen-presentation function by human gammadelta T Cells. Science 309(5732):264–268PubMedCrossRefGoogle Scholar
  16. 16.
    Bumgardner GL, Matas AJ et al (1990) Comparison of in vivo and in vitro immune response to purified hepatocytes. Transplantation 49(2):429–436PubMedCrossRefGoogle Scholar
  17. 17.
    Callery MP, Kamei T et al (1989) The effect of portacaval shunt on delayed-hypersensitivity responses following antigen feeding. J Surg Res 46(4):391–394PubMedCrossRefGoogle Scholar
  18. 18.
    Calne RY, Sells RA et al (1969) Induction of immunological tolerance by porcine liver allografts. Nature 223(5205):472–476PubMedCrossRefGoogle Scholar
  19. 19.
    Cantor HM, Dumont AE (1967) Hepatic suppression of sensitization to antigen absorbed into the portal system. Nature 215(5102):744–745PubMedCrossRefGoogle Scholar
  20. 20.
    Cao O, Dobrzynski E et al (2007) Induction and role of regulatory CD4+ CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer. Blood 110(4):1132–1140PubMedCrossRefGoogle Scholar
  21. 21.
    Carding SR, Egan PJ (2002) Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2(5):336–345PubMedCrossRefGoogle Scholar
  22. 22.
    Chen Y, Ong CR et al (2001) Induction of immune hyporesponsiveness after portal vein immunization with ovalbumin. Surgery 129(1):66–75PubMedCrossRefGoogle Scholar
  23. 23.
    Chen M, Tabaczewski P et al (2005) Hepatocytes express abundant surface class I MHC and efficiently use transporter associated with antigen processing, tapasin, and low molecular weight polypeptide proteasome subunit components of antigen processing and presentation pathway. J Immunol 175(2):1047–1055PubMedGoogle Scholar
  24. 24.
    Chen L, Calomeni E et al (2007) Natural killer dendritic cells are an intermediate of developing dendritic cells. J Leukoc Biol 81(6):1422–1433PubMedCrossRefGoogle Scholar
  25. 25.
    Chen XM, O’Hara SP et al (2008) The immunobiology of cholangiocytes. Immunol Cell Biol 86(6):497–505PubMedCrossRefGoogle Scholar
  26. 26.
    Codarri L, Vallotton L et al (2007) Expansion and tissue infiltration of an allospecific CD4+ CD25+ CD45RO+ IL-7Ralphahigh cell population in solid organ transplant recipients. J Exp Med 204(7):1533–1541PubMedCrossRefGoogle Scholar
  27. 27.
    Cooper MA, Fehniger TA et al (2001) Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 97(10):3146–3151PubMedCrossRefGoogle Scholar
  28. 28.
    Coquet JM, Chakravarti S et al (2008) Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4− NK1.1− NKT cell population. Proc Natl Acad Sci U S A 105(32):11287–11292PubMedCrossRefGoogle Scholar
  29. 29.
    Crispe IN (2003) Hepatic T cells and liver tolerance. Nat Rev Immunol 3(1):51–62PubMedCrossRefGoogle Scholar
  30. 30.
    Crispe IN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27:147–163PubMedCrossRefGoogle Scholar
  31. 31.
    Crispe IN, Mehal WZ (1996) Strange brew: T cells in the liver. Immunol Today 17(11):522–525PubMedCrossRefGoogle Scholar
  32. 32.
    Crispe IN, Giannandrea M et al (2006) Cellular and molecular mechanisms of liver tolerance. Immunol Rev 213:101–118PubMedCrossRefGoogle Scholar
  33. 33.
    Curry MP, Golden-Mason L et al (2000) Expansion of peripheral blood CD5+ B cells is associated with mild disease in chronic hepatitis C virus infection. J Hepatol 32(1):121–125PubMedCrossRefGoogle Scholar
  34. 34.
    Curry MP, Golden-Mason L et al (2003) Expansion of innate CD5pos B cells expressing high levels of CD81 in hepatitis C virus infected liver. J Hepatol 38(5):642–650PubMedCrossRefGoogle Scholar
  35. 35.
    Dalloul A (2009) CD5: a safeguard against autoimmunity and a shield for cancer cells. Autoimmun Rev 8(4):349–353PubMedCrossRefGoogle Scholar
  36. 36.
    Deignan T, Curry MP, Doherty DG, Golden Mason L, Volkov Y, Norris S, Nolan N, Traynor O, McEntee G, Hegarty JE, O’Farrelly C (2002) (2002) Decrease in hepatic CD56+ T cells and Vα24+ natural killer T cells in chronic hepatitis C viral infection. J Hepatol 37:101–108PubMedCrossRefGoogle Scholar
  37. 37.
    Demirkiran A, Kok A et al (2006) Low circulating regulatory T-cell levels after acute rejection in liver transplantation. Liver Transpl 12(2):277–284PubMedCrossRefGoogle Scholar
  38. 38.
    Doherty DG, O’Farrelly C (2000) Innate and adaptive lymphoid cells in the human liver. Immunol Rev 174:5–20PubMedCrossRefGoogle Scholar
  39. 39.
    Doherty D, O’Farrelly C (2001) Dendritic cells: regulators of hepatic immunity or tolerance. J Hepatol 34:156–160 PMID 11211894PubMedCrossRefGoogle Scholar
  40. 40.
    Doherty D, Norris S, Madrigal-Estebas L, McEntee G, Traynor O, Hegarty JE, O'Farrelly C (1999) The human liver contains multiple populations of NK cells, T cells and CD3+ CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2 and Th0 cytokine secretion patterns. J Immunol 163:2314–2321PubMedGoogle Scholar
  41. 41.
    Duan B, Morel L (2006) Role of B-1a cells in autoimmunity. Autoimmun Rev 5(6):403–408PubMedCrossRefGoogle Scholar
  42. 42.
    Emoto M, Kaufmann SH (2003) Liver NKT cells: an account of heterogeneity. Trends Immunol 24(7):364–369PubMedCrossRefGoogle Scholar
  43. 43.
    Erhardt A, Biburger M et al (2007) IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology 45(2):475–485PubMedCrossRefGoogle Scholar
  44. 44.
    Fraser R, Dobbs BR et al (1995) Lipoproteins and the liver sieve: the role of the fenestrated sinusoidal endothelium in lipoprotein metabolism, atherosclerosis, and cirrhosis. Hepatology 21(3):863–874PubMedGoogle Scholar
  45. 45.
    Gao B, Jeong WI et al (2008) Liver: an organ with predominant innate immunity. Hepatology 47(2):729–736PubMedCrossRefGoogle Scholar
  46. 46.
    Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 114(10):1379–1388PubMedGoogle Scholar
  47. 47.
    Golden-Mason L, Rosen HR (2006) Natural killer cells: primary targets for hepatitis C virus immune evasion strategies. Liver Transpl 12:363–372PubMedCrossRefGoogle Scholar
  48. 48.
    Godfrey DI, MacDonald HR et al (2004) NKT cells: what’s in a name? Nat Rev Immunol 4(3):231–237PubMedCrossRefGoogle Scholar
  49. 49.
    Gorczynski RM, Chan Z et al (1994) Prolongation of rat small bowel or renal allograft survival by pretransplant transfusion and/or by varying the route of allograft venous drainage. Transplantation 58(7):816–820PubMedCrossRefGoogle Scholar
  50. 50.
    Gregoire C, Chasson L et al (2007) The trafficking of natural killer cells. Immunol Rev 220:169–182PubMedCrossRefGoogle Scholar
  51. 51.
    Gregory SH, Wing EJ (1990) Accessory function of Kupffer cells in the antigen-specific blastogenic response of an L3T4+ T-lymphocyte clone to Listeria monocytogenes. Infect Immun 58(7):2313–2319PubMedGoogle Scholar
  52. 52.
    Gregory SH, Wing EJ (1998) Neutrophil–Kupffer-cell interaction in host defenses to systemic infections. Immunol Today 19(11):507–510PubMedCrossRefGoogle Scholar
  53. 53.
    Gregory SH, Sagnimeni AJ et al (1996) Bacteria in the bloodstream are trapped in the liver and killed by immigrating neutrophils. J Immunol 157(6):2514–2520PubMedGoogle Scholar
  54. 54.
    Grewe M, Duyster J et al (1992) Prostaglandin D2 and E2 syntheses in rat Kupffer cells are antagonistically regulated by lipopolysaccharide and phorbol ester. Biol Chem Hoppe Seyler 373(8):655–664PubMedGoogle Scholar
  55. 55.
    Hagmann W, Hacker HJ et al (1992) Resident mast cells are the main initiators of anaphylactic leukotriene production in the liver. Hepatology 16(6):1477–1484PubMedCrossRefGoogle Scholar
  56. 56.
    Hamada S, Umemura M et al (2008) IL-17A produced by gammadelta T cells plays a critical role in innate immunity against Listeria monocytogenes infection in the liver. J Immunol 181(5):3456–3463PubMedGoogle Scholar
  57. 57.
    Hayakawa K, Asano M et al (1999) Positive selection of natural autoreactive B cells. Science 285(5424):113–116PubMedCrossRefGoogle Scholar
  58. 58.
    Herberman RB, Nunn ME, Holden HT, Lavrin DH (1975) Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer 16(2):230–239PubMedCrossRefGoogle Scholar
  59. 59.
    Hsieh CL, Obara H et al (2002) NK cells and transplantation. Transpl Immunol 9(2–4):111–114PubMedCrossRefGoogle Scholar
  60. 60.
    Hsu W, Shu SA et al (2007) The current immune function of hepatic dendritic cells. Cell Mol Immunol 4(5):321–328PubMedGoogle Scholar
  61. 61.
    Huang L, Soldevila G et al (1994) The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo. Immunity 1(9):741–749PubMedCrossRefGoogle Scholar
  62. 62.
    Itoh Y, Morita A et al (2001) Time course profile and cell-type-specific production of monokine induced by interferon-gamma in concanavalin A-induced hepatic injury in mice: comparative study with interferon-inducible protein-10. Scand J Gastroenterol 36(12):1344–1351PubMedCrossRefGoogle Scholar
  63. 63.
    Jomantaite I, Dikopoulos N et al (2004) Hepatic dendritic cell subsets in the mouse. Eur J Immunol 34(2):355–365PubMedCrossRefGoogle Scholar
  64. 64.
    Kamada N, Wight DG (1984) Antigen-specific immunosuppression induced by liver transplantation in the rat. Transplantation 38(3):217–221PubMedCrossRefGoogle Scholar
  65. 65.
    Kenna T, Golden-Mason L, Norris S, Hegarty JE, O'Farrelly C, Doherty D (2004) Distinct subpopulations of γδT cells are present in normal and tumor-bearing human liver. Clin Immunol 113(1):56–63 PMID 15380530PubMedCrossRefGoogle Scholar
  66. 66.
    Klugewitz K, Adams DH et al (2004) The composition of intrahepatic lymphocytes: shaped by selective recruitment? Trends Immunol 25(11):590–594PubMedCrossRefGoogle Scholar
  67. 67.
    Klugewitz K, Blumenthal-Barby F et al (2004) The spectrum of lymphoid subsets preferentially recruited into the liver reflects that of resident populations. Immunol Lett 93(2–3):159–162PubMedCrossRefGoogle Scholar
  68. 68.
    Knolle PA, Gerken G (2000) Local control of the immune response in the liver. Immunol Rev 174:21–34PubMedCrossRefGoogle Scholar
  69. 69.
    Knolle PA, Limmer A (2001) Neighborhood politics: the immunoregulatory function of organ-resident liver endothelial cells. Trends Immunol 22(8):432–437PubMedCrossRefGoogle Scholar
  70. 70.
    Knolle P, Schlaak J et al (1995) Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol 22(2):226–229PubMedCrossRefGoogle Scholar
  71. 71.
    Knolle PA, Uhrig A et al (1998) IL-10 down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells through decreased antigen uptake via the mannose receptor and lowered surface expression of accessory molecules. Clin Exp Immunol 114(3):427–433PubMedCrossRefGoogle Scholar
  72. 72.
    Knolle PA, Schmitt E et al (1999) Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology 116(6):1428–1440PubMedCrossRefGoogle Scholar
  73. 73.
    Koch SD, Uss E et al (2008) Alloantigen-induced regulatory CD8(+)CD103(+) T cells. Hum Immunol 69:737–744PubMedCrossRefGoogle Scholar
  74. 74.
    Kolios G, Valatas V et al (2006) Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol 12(46):7413–7420PubMedGoogle Scholar
  75. 75.
    Kono H, Fujii H et al (2002) Functional heterogeneity of the Kupffer cell population is involved in the mechanism of gadolinium chloride in rats administered endotoxin. J Surg Res 106(1):179–187PubMedCrossRefGoogle Scholar
  76. 76.
    Kono H, Fujii H et al (2005) Role of Kupffer cells in lung injury in rats administered endotoxin 1. J Surg Res 129(2):176–189PubMedCrossRefGoogle Scholar
  77. 77.
    Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, Chuang YH, Nakamura T, Saito S, Shimoda S, Tanaka A, Bowlus CL, Takano Y, Ansari AA, Coppel RL, Gershwin ME (2006) Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 43(4):729–737PubMedCrossRefGoogle Scholar
  78. 78.
    Lan RY, Salunga TL et al (2009) Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun 32(1):43–51PubMedCrossRefGoogle Scholar
  79. 79.
    Lankester AC, van Schijndel GM et al (1994) CD5 is associated with the human B cell antigen receptor complex. Eur J Immunol 24(4):812–816PubMedCrossRefGoogle Scholar
  80. 80.
    Li W, Kuhr CS, Zheng XX, Carper K, Thomson AW, Reyes JD, Perkins JD (2008) New insights into mechanisms of spontaneous liver transplant tolerance: the role of Foxp3-expressing CD25+CD4+ regulatory T cells. Am J Transplant 8(8):1639–1651PubMedCrossRefGoogle Scholar
  81. 81.
    Lian ZX, Okada T et al (2003) Heterogeneity of dendritic cells in the mouse liver: identification and characterization of four distinct populations. J Immunol 170(5):2323–2330PubMedGoogle Scholar
  82. 82.
    Liew FY (2002) T(H) 1 and T(H) 2 cells: a historical perspective. Nat Rev Immunol 2(1):55–60PubMedCrossRefGoogle Scholar
  83. 83.
    Limmer A, Ohl J et al (2000) Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med 6(12):1348–1354PubMedCrossRefGoogle Scholar
  84. 84.
    Lloyd CM, Phillips AR et al (2008) Three-colour fluorescence immunohistochemistry reveals the diversity of cells staining for macrophage markers in murine spleen and liver. J Immunol Methods 334(1–2):70–81PubMedCrossRefGoogle Scholar
  85. 85.
    Lodoen MB, Lanier LL (2006) Natural killer cells as an initial defense against pathogens. Curr Opin Immunol 18(4):391–398PubMedCrossRefGoogle Scholar
  86. 86.
    Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D (1975) Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. Int J Cancer 16(2):230–239CrossRefGoogle Scholar
  87. 87.
    Lumsden AB, Henderson JM et al (1988) Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology 8(2):232–236PubMedCrossRefGoogle Scholar
  88. 88.
    MacPhee PJ, Schmidt EE et al (1992) Evidence for Kupffer cell migration along liver sinusoids, from high-resolution in vivo microscopy. Am J Physiol 263(1 Pt 1):G17–G23PubMedGoogle Scholar
  89. 89.
    MacPhee PJ, Schmidt EE et al (1995) Intermittence of blood flow in liver sinusoids, studied by high-resolution in vivo microscopy. Am J Physiol 269(5 Pt 1):G692–G698PubMedGoogle Scholar
  90. 90.
    Malone F, Carper K et al (2009) gammadeltaT cells are involved in liver transplant tolerance. Transplant Proc 41(1):233–235PubMedCrossRefGoogle Scholar
  91. 91.
    Mandal M, Chen XR et al (1998) Tissue distribution, regulation and intracellular localization of murine CD1 molecules. Mol Immunol 35(9):525–536PubMedCrossRefGoogle Scholar
  92. 92.
    Martin F, Kearney JF (2000) Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity 12(1):39–49PubMedCrossRefGoogle Scholar
  93. 93.
    Martin F, Kearney JF (2001) B1 cells: similarities and differences with other B cell subsets. Curr Opin Immunol 13(2):195–201PubMedCrossRefGoogle Scholar
  94. 94.
    Mohrs K, Harris DP et al (2005) Systemic dissemination and persistence of Th2 and type 2 cells in response to infection with a strictly enteric nematode parasite. J Immunol 175(8):5306–5313PubMedGoogle Scholar
  95. 95.
    Monteverde A, Ballare M et al (1997) Hepatic lymphoid aggregates in chronic hepatitis C and mixed cryoglobulinemia. Springer Semin Immunopathol 19(1):99–110PubMedCrossRefGoogle Scholar
  96. 96.
    Morahan G, Brennan FE et al (1989) Expression in transgenic mice of class I histocompatibility antigens controlled by the metallothionein promoter. Proc Natl Acad Sci U S A 86(10):3782–3786PubMedCrossRefGoogle Scholar
  97. 97.
    Norris S, Collins C, Doherty D, Smith F, McEntee G, Traynor O, Nolan N, Hegarty J, O’Farrelly C (1998) Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J Hepatol 28:84–90 PMID 9537869PubMedCrossRefGoogle Scholar
  98. 98.
    Novobrantseva TI, Majeau GR et al (2005) Attenuated liver fibrosis in the absence of B cells. J Clin Invest 115(11):3072–3082PubMedCrossRefGoogle Scholar
  99. 99.
    O’Garra A, Chang R et al (1992) Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10. Eur J Immunol 22(3):711–717PubMedCrossRefGoogle Scholar
  100. 100.
    O’Keeffe C, Baird AW, Nolan N, McCormick PA (2002) Mast cell hyperplasia in chronic rejection after liver transplantation. Liver Transpl 8(1):50–57PubMedCrossRefGoogle Scholar
  101. 101.
    Ogasawara K, Takeda K et al (1998) Involvement of NK1+ T cells and their IFN-gamma production in the generalized Shwartzman reaction. J Immunol 160(7):3522–3527PubMedGoogle Scholar
  102. 102.
    Prickett TC, McKenzie JL et al (1988) Characterization of interstitial dendritic cells in human liver. Transplantation 46(5):754–761PubMedCrossRefGoogle Scholar
  103. 103.
    Rao VK, Burris DE et al (1988) Evidence that donor spleen cells administered through the portal vein prolong the survival of cardiac allografts in rats. Transplantation 45(6):1145–1146PubMedCrossRefGoogle Scholar
  104. 104.
    Raulet DH, Vance RE (2006) Self-tolerance of natural killer cells. Nat Rev Immunol 6(7):520–531PubMedCrossRefGoogle Scholar
  105. 105.
    Rioux KP, Sharkey KA et al (1996) Hepatic mucosal mast cell hyperplasia in rats with secondary biliary cirrhosis. Hepatology 23(4):888–895PubMedCrossRefGoogle Scholar
  106. 106.
    Rong G, Zhou Y et al (2009) Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine profile and peripheral cell population. Clin Exp Immunol 156(2):217–225PubMedCrossRefGoogle Scholar
  107. 107.
    Ruiter DJ, van der Meulen J et al (1981) Uptake by liver cells of endotoxin following its intravenous injection. Lab Invest 45(1):38–45PubMedGoogle Scholar
  108. 108.
    Sakaguchi S, Powrie F (2007) Emerging challenges in regulatory T cell function and biology. Science 317(5838):627–629PubMedCrossRefGoogle Scholar
  109. 109.
    Santodomingo-Garzon T, Han J et al (2009) Natural killer T cells regulate the homing of chemokine CXC receptor 3-positive regulatory T cells to the liver in mice. Hepatology 49(4):1267–1276PubMedCrossRefGoogle Scholar
  110. 110.
    Shapiro AM, Lakey JR et al (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343(4):230–238PubMedCrossRefGoogle Scholar
  111. 111.
    Shi J, Fujieda H et al (1996) Apoptosis of neutrophils and their elimination by Kupffer cells in rat liver. Hepatology 24(5):1256–1263PubMedCrossRefGoogle Scholar
  112. 112.
    Shi J, Gilbert GE et al (2001) Role of the liver in regulating numbers of circulating neutrophils. Blood 98(4):1226–1230PubMedCrossRefGoogle Scholar
  113. 113.
    Takeda K, Smyth MJ et al (2002) Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 195(2):161–169PubMedCrossRefGoogle Scholar
  114. 114.
    Tatu C, Ye J et al (1999) Selection at multiple checkpoints focuses V(H) 12 B cell differentiation toward a single B-1 cell specificity. J Exp Med 190(7):903–914PubMedCrossRefGoogle Scholar
  115. 115.
    Thomson CW, Lee BP et al (2006) Double-negative regulatory T cells: non-conventional regulators. Immunol Res 35(1–2):163–178PubMedCrossRefGoogle Scholar
  116. 116.
    Toyabe S, Seki S et al (1997) Requirement of IL-4 and liver NK1+ T cells for concanavalin A-induced hepatic injury in mice. J Immunol 159(3):1537–1542PubMedGoogle Scholar
  117. 117.
    Tu Z, Bozorgzadeh A, Crispe IN, Orloff MS (2007) The activation state of human intrahepatic lymphocytes. Clin Exp Immunol 149(1):186–193PubMedGoogle Scholar
  118. 118.
    Unitt E, Rushbrook SM et al (2005) Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 41(4):722–730PubMedCrossRefGoogle Scholar
  119. 119.
    Wallin RP, Screpanti V et al (2003) Regulation of perforin-independent NK cell-mediated cytotoxicity. Eur J Immunol 33(10):2727–2735PubMedCrossRefGoogle Scholar
  120. 120.
    Ward SM, Fox BC et al (2007) Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection. J Hepatol 47(3):316–324PubMedCrossRefGoogle Scholar
  121. 121.
    Warren A, Le Couteur DG et al (2006) T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology 44(5):1182–1190PubMedCrossRefGoogle Scholar
  122. 122.
    Webster DP, Klenerman P et al (2009) Development of novel treatments for hepatitis C. Lancet Infect Dis 9(2):108–117PubMedCrossRefGoogle Scholar
  123. 123.
    Winau F, Quack C et al (2008) Starring stellate cells in liver immunology. Curr Opin Immunol 20(1):68–74PubMedCrossRefGoogle Scholar
  124. 124.
    Wisse E (1970) An electron microscopic study of the fenestrated endothelial lining of rat liver sinusoids. J Ultrastruct Res 31(1):125–150PubMedCrossRefGoogle Scholar
  125. 125.
    Wisse E, De Zanger RB et al (1985) The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 5(4):683–692PubMedCrossRefGoogle Scholar
  126. 126.
    Xu D, Fu J et al (2006) Circulating and liver resident CD4+ CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Immunol 177(1):739–747PubMedGoogle Scholar
  127. 127.
    Yamagiwa S, Sugahara S et al (1998) The primary site of CD4–8− B220+ alphabeta T cells in lpr mice: the appendix in normal mice. J Immunol 160(6):2665–2674PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Eszter Nemeth
    • 1
  • Alan W. Baird
    • 1
  • Cliona O’Farrelly
    • 2
  1. 1.UCD Conway Institute and School of Agriculture, Food Science and Veterinary Medicine, University College DublinDublinIreland
  2. 2.School of Biochemistry and Immunology and School of MedicineTrinity College DublinDublinIreland

Personalised recommendations