Skip to main content

Advertisement

SpringerLink
Log in

Microanatomy of the liver immune system

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

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.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  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):1607–1616

    Article  CAS  PubMed  Google Scholar 

  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):963–972

    CAS  PubMed  Google Scholar 

  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):1042–1054

    Article  CAS  PubMed  Google Scholar 

  4. Balter M (2000) Malaria. Can WHO roll back malaria? Science 290(5491):430

    Article  CAS  PubMed  Google Scholar 

  5. Befus D, Fujimaki H et al (1988) Mast cell polymorphisms. Present concepts, future directions. Dig Dis Sci 33(3 Suppl):16S–24S

    Article  CAS  PubMed  Google Scholar 

  6. Bendelac A, Savage PB et al (2007) The biology of NKT cells. Annu Rev Immunol 25:297–336

    Article  CAS  PubMed  Google Scholar 

  7. Berland R, Wortis HH (2002) Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol 20:253–300

    Article  CAS  PubMed  Google Scholar 

  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):221–236

    Article  CAS  PubMed  Google Scholar 

  9. Bettelli E, Korn T et al (2007) Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 19(6):652–657

    Article  CAS  PubMed  Google Scholar 

  10. Bilzer M, Roggel F et al (2006) Role of Kupffer cells in host defense and liver disease. Liver Int 26(10):1175–1186

    Article  CAS  PubMed  Google Scholar 

  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):320–329

    Article  CAS  PubMed  Google Scholar 

  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 48:1954–1963

    Article  CAS  PubMed  Google Scholar 

  13. Born WK, Reardon CL et al (2006) The function of gammadelta T cells in innate immunity. Curr Opin Immunol 18(1):31–38

    Article  CAS  PubMed  Google Scholar 

  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):283–290

    Article  CAS  Google Scholar 

  15. Brandes M, Willimann K et al (2005) Professional antigen-presentation function by human gammadelta T Cells. Science 309(5732):264–268

    Article  CAS  PubMed  Google Scholar 

  16. Bumgardner GL, Matas AJ et al (1990) Comparison of in vivo and in vitro immune response to purified hepatocytes. Transplantation 49(2):429–436

    Article  CAS  PubMed  Google Scholar 

  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):391–394

    Article  CAS  PubMed  Google Scholar 

  18. Calne RY, Sells RA et al (1969) Induction of immunological tolerance by porcine liver allografts. Nature 223(5205):472–476

    Article  CAS  PubMed  Google Scholar 

  19. Cantor HM, Dumont AE (1967) Hepatic suppression of sensitization to antigen absorbed into the portal system. Nature 215(5102):744–745

    Article  CAS  PubMed  Google Scholar 

  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):1132–1140

    Article  CAS  PubMed  Google Scholar 

  21. Carding SR, Egan PJ (2002) Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2(5):336–345

    Article  CAS  PubMed  Google Scholar 

  22. Chen Y, Ong CR et al (2001) Induction of immune hyporesponsiveness after portal vein immunization with ovalbumin. Surgery 129(1):66–75

    Article  CAS  PubMed  Google Scholar 

  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):1047–1055

    CAS  PubMed  Google Scholar 

  24. Chen L, Calomeni E et al (2007) Natural killer dendritic cells are an intermediate of developing dendritic cells. J Leukoc Biol 81(6):1422–1433

    Article  CAS  PubMed  Google Scholar 

  25. Chen XM, O’Hara SP et al (2008) The immunobiology of cholangiocytes. Immunol Cell Biol 86(6):497–505

    Article  CAS  PubMed  Google Scholar 

  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):1533–1541

    Article  CAS  PubMed  Google Scholar 

  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):3146–3151

    Article  CAS  PubMed  Google Scholar 

  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):11287–11292

    Article  CAS  PubMed  Google Scholar 

  29. Crispe IN (2003) Hepatic T cells and liver tolerance. Nat Rev Immunol 3(1):51–62

    Article  CAS  PubMed  Google Scholar 

  30. Crispe IN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27:147–163

    Article  CAS  PubMed  Google Scholar 

  31. Crispe IN, Mehal WZ (1996) Strange brew: T cells in the liver. Immunol Today 17(11):522–525

    Article  CAS  PubMed  Google Scholar 

  32. Crispe IN, Giannandrea M et al (2006) Cellular and molecular mechanisms of liver tolerance. Immunol Rev 213:101–118

    Article  PubMed  Google Scholar 

  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):121–125

    Article  CAS  PubMed  Google Scholar 

  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):642–650

    Article  CAS  PubMed  Google Scholar 

  35. Dalloul A (2009) CD5: a safeguard against autoimmunity and a shield for cancer cells. Autoimmun Rev 8(4):349–353

    Article  CAS  PubMed  Google Scholar 

  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 37:101–108

    Article  CAS  PubMed  Google Scholar 

  37. Demirkiran A, Kok A et al (2006) Low circulating regulatory T-cell levels after acute rejection in liver transplantation. Liver Transpl 12(2):277–284

    Article  PubMed  Google Scholar 

  38. Doherty DG, O’Farrelly C (2000) Innate and adaptive lymphoid cells in the human liver. Immunol Rev 174:5–20

    Article  CAS  PubMed  Google Scholar 

  39. Doherty D, O’Farrelly C (2001) Dendritic cells: regulators of hepatic immunity or tolerance. J Hepatol 34:156–160 PMID 11211894

    Article  CAS  PubMed  Google Scholar 

  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 163:2314–2321

    CAS  PubMed  Google Scholar 

  41. Duan B, Morel L (2006) Role of B-1a cells in autoimmunity. Autoimmun Rev 5(6):403–408

    Article  CAS  PubMed  Google Scholar 

  42. Emoto M, Kaufmann SH (2003) Liver NKT cells: an account of heterogeneity. Trends Immunol 24(7):364–369

    Article  CAS  PubMed  Google Scholar 

  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):475–485

    Article  CAS  PubMed  Google Scholar 

  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):863–874

    CAS  PubMed  Google Scholar 

  45. Gao B, Jeong WI et al (2008) Liver: an organ with predominant innate immunity. Hepatology 47(2):729–736

    Article  CAS  PubMed  Google Scholar 

  46. Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 114(10):1379–1388

    CAS  PubMed  Google Scholar 

  47. Golden-Mason L, Rosen HR (2006) Natural killer cells: primary targets for hepatitis C virus immune evasion strategies. Liver Transpl 12:363–372

    Article  PubMed  Google Scholar 

  48. Godfrey DI, MacDonald HR et al (2004) NKT cells: what’s in a name? Nat Rev Immunol 4(3):231–237

    Article  CAS  PubMed  Google Scholar 

  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):816–820

    Article  CAS  PubMed  Google Scholar 

  50. Gregoire C, Chasson L et al (2007) The trafficking of natural killer cells. Immunol Rev 220:169–182

    Article  CAS  PubMed  Google Scholar 

  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):2313–2319

    CAS  PubMed  Google Scholar 

  52. Gregory SH, Wing EJ (1998) Neutrophil–Kupffer-cell interaction in host defenses to systemic infections. Immunol Today 19(11):507–510

    Article  CAS  PubMed  Google Scholar 

  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):2514–2520

    CAS  PubMed  Google Scholar 

  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):655–664

    CAS  PubMed  Google Scholar 

  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):1477–1484

    Article  CAS  PubMed  Google Scholar 

  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):3456–3463

    CAS  PubMed  Google Scholar 

  57. Hayakawa K, Asano M et al (1999) Positive selection of natural autoreactive B cells. Science 285(5424):113–116

    Article  CAS  PubMed  Google Scholar 

  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):230–239

    Article  CAS  PubMed  Google Scholar 

  59. Hsieh CL, Obara H et al (2002) NK cells and transplantation. Transpl Immunol 9(2–4):111–114

    Article  CAS  PubMed  Google Scholar 

  60. Hsu W, Shu SA et al (2007) The current immune function of hepatic dendritic cells. Cell Mol Immunol 4(5):321–328

    CAS  PubMed  Google Scholar 

  61. Huang L, Soldevila G et al (1994) The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo. Immunity 1(9):741–749

    Article  CAS  PubMed  Google Scholar 

  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):1344–1351

    Article  CAS  PubMed  Google Scholar 

  63. Jomantaite I, Dikopoulos N et al (2004) Hepatic dendritic cell subsets in the mouse. Eur J Immunol 34(2):355–365

    Article  CAS  PubMed  Google Scholar 

  64. Kamada N, Wight DG (1984) Antigen-specific immunosuppression induced by liver transplantation in the rat. Transplantation 38(3):217–221

    Article  CAS  PubMed  Google Scholar 

  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 15380530

    Article  CAS  PubMed  Google Scholar 

  66. Klugewitz K, Adams DH et al (2004) The composition of intrahepatic lymphocytes: shaped by selective recruitment? Trends Immunol 25(11):590–594

    Article  CAS  PubMed  Google Scholar 

  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):159–162

    Article  CAS  PubMed  Google Scholar 

  68. Knolle PA, Gerken G (2000) Local control of the immune response in the liver. Immunol Rev 174:21–34

    Article  CAS  PubMed  Google Scholar 

  69. Knolle PA, Limmer A (2001) Neighborhood politics: the immunoregulatory function of organ-resident liver endothelial cells. Trends Immunol 22(8):432–437

    Article  CAS  PubMed  Google Scholar 

  70. Knolle P, Schlaak J et al (1995) Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J Hepatol 22(2):226–229

    Article  CAS  PubMed  Google Scholar 

  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):427–433

    Article  CAS  PubMed  Google Scholar 

  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):1428–1440

    Article  CAS  PubMed  Google Scholar 

  73. Koch SD, Uss E et al (2008) Alloantigen-induced regulatory CD8(+)CD103(+) T cells. Hum Immunol 69:737–744

    Article  CAS  PubMed  Google Scholar 

  74. Kolios G, Valatas V et al (2006) Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol 12(46):7413–7420

    CAS  PubMed  Google Scholar 

  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):179–187

    Article  CAS  PubMed  Google Scholar 

  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):176–189

    Article  CAS  PubMed  Google Scholar 

  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):729–737

    Article  PubMed  Google Scholar 

  78. Lan RY, Salunga TL et al (2009) Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun 32(1):43–51

    Article  CAS  PubMed  Google Scholar 

  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):812–816

    Article  CAS  PubMed  Google Scholar 

  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):1639–1651

    Article  CAS  PubMed  Google Scholar 

  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):2323–2330

    CAS  PubMed  Google Scholar 

  82. Liew FY (2002) T(H) 1 and T(H) 2 cells: a historical perspective. Nat Rev Immunol 2(1):55–60

    Article  CAS  PubMed  Google Scholar 

  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):1348–1354

    Article  CAS  PubMed  Google Scholar 

  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):70–81

    Article  CAS  PubMed  Google Scholar 

  85. Lodoen MB, Lanier LL (2006) Natural killer cells as an initial defense against pathogens. Curr Opin Immunol 18(4):391–398

    Article  CAS  PubMed  Google Scholar 

  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):230–239

    Article  Google Scholar 

  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):232–236

    Article  CAS  PubMed  Google Scholar 

  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–G23

    CAS  PubMed  Google Scholar 

  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–G698

    CAS  PubMed  Google Scholar 

  90. Malone F, Carper K et al (2009) gammadeltaT cells are involved in liver transplant tolerance. Transplant Proc 41(1):233–235

    Article  CAS  PubMed  Google Scholar 

  91. Mandal M, Chen XR et al (1998) Tissue distribution, regulation and intracellular localization of murine CD1 molecules. Mol Immunol 35(9):525–536

    Article  CAS  PubMed  Google Scholar 

  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):39–49

    Article  CAS  PubMed  Google Scholar 

  93. Martin F, Kearney JF (2001) B1 cells: similarities and differences with other B cell subsets. Curr Opin Immunol 13(2):195–201

    Article  CAS  PubMed  Google Scholar 

  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):5306–5313

    CAS  PubMed  Google Scholar 

  95. Monteverde A, Ballare M et al (1997) Hepatic lymphoid aggregates in chronic hepatitis C and mixed cryoglobulinemia. Springer Semin Immunopathol 19(1):99–110

    Article  CAS  PubMed  Google Scholar 

  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):3782–3786

    Article  CAS  PubMed  Google Scholar 

  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 9537869

    Article  CAS  PubMed  Google Scholar 

  98. Novobrantseva TI, Majeau GR et al (2005) Attenuated liver fibrosis in the absence of B cells. J Clin Invest 115(11):3072–3082

    Article  CAS  PubMed  Google Scholar 

  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):711–717

    Article  PubMed  Google Scholar 

  100. O’Keeffe C, Baird AW, Nolan N, McCormick PA (2002) Mast cell hyperplasia in chronic rejection after liver transplantation. Liver Transpl 8(1):50–57

    Article  PubMed  Google Scholar 

  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):3522–3527

    CAS  PubMed  Google Scholar 

  102. Prickett TC, McKenzie JL et al (1988) Characterization of interstitial dendritic cells in human liver. Transplantation 46(5):754–761

    Article  CAS  PubMed  Google Scholar 

  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):1145–1146

    Article  CAS  PubMed  Google Scholar 

  104. Raulet DH, Vance RE (2006) Self-tolerance of natural killer cells. Nat Rev Immunol 6(7):520–531

    Article  CAS  PubMed  Google Scholar 

  105. Rioux KP, Sharkey KA et al (1996) Hepatic mucosal mast cell hyperplasia in rats with secondary biliary cirrhosis. Hepatology 23(4):888–895

    Article  CAS  PubMed  Google Scholar 

  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):217–225

    Article  CAS  PubMed  Google Scholar 

  107. Ruiter DJ, van der Meulen J et al (1981) Uptake by liver cells of endotoxin following its intravenous injection. Lab Invest 45(1):38–45

    CAS  PubMed  Google Scholar 

  108. Sakaguchi S, Powrie F (2007) Emerging challenges in regulatory T cell function and biology. Science 317(5838):627–629

    Article  CAS  PubMed  Google Scholar 

  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):1267–1276

    Article  CAS  PubMed  Google Scholar 

  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):230–238

    Article  CAS  PubMed  Google Scholar 

  111. Shi J, Fujieda H et al (1996) Apoptosis of neutrophils and their elimination by Kupffer cells in rat liver. Hepatology 24(5):1256–1263

    Article  CAS  PubMed  Google Scholar 

  112. Shi J, Gilbert GE et al (2001) Role of the liver in regulating numbers of circulating neutrophils. Blood 98(4):1226–1230

    Article  CAS  PubMed  Google Scholar 

  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):161–169

    Article  CAS  PubMed  Google Scholar 

  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):903–914

    Article  CAS  PubMed  Google Scholar 

  115. Thomson CW, Lee BP et al (2006) Double-negative regulatory T cells: non-conventional regulators. Immunol Res 35(1–2):163–178

    Article  CAS  PubMed  Google Scholar 

  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):1537–1542

    CAS  PubMed  Google Scholar 

  117. Tu Z, Bozorgzadeh A, Crispe IN, Orloff MS (2007) The activation state of human intrahepatic lymphocytes. Clin Exp Immunol 149(1):186–193

    CAS  PubMed  Google Scholar 

  118. Unitt E, Rushbrook SM et al (2005) Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 41(4):722–730

    Article  CAS  PubMed  Google Scholar 

  119. Wallin RP, Screpanti V et al (2003) Regulation of perforin-independent NK cell-mediated cytotoxicity. Eur J Immunol 33(10):2727–2735

    Article  CAS  PubMed  Google Scholar 

  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):316–324

    Article  CAS  PubMed  Google Scholar 

  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):1182–1190

    Article  CAS  PubMed  Google Scholar 

  122. Webster DP, Klenerman P et al (2009) Development of novel treatments for hepatitis C. Lancet Infect Dis 9(2):108–117

    Article  CAS  PubMed  Google Scholar 

  123. Winau F, Quack C et al (2008) Starring stellate cells in liver immunology. Curr Opin Immunol 20(1):68–74

    Article  CAS  PubMed  Google Scholar 

  124. Wisse E (1970) An electron microscopic study of the fenestrated endothelial lining of rat liver sinusoids. J Ultrastruct Res 31(1):125–150

    Article  CAS  PubMed  Google Scholar 

  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):683–692

    Article  CAS  PubMed  Google Scholar 

  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):739–747

    CAS  PubMed  Google Scholar 

  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):2665–2674

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. UCD Conway Institute and School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Dublin, Ireland

    Eszter Nemeth & Alan W. Baird

  2. School of Biochemistry and Immunology and School of Medicine, Trinity College Dublin, Dublin, Ireland

    Cliona O’Farrelly

Authors
  1. Eszter Nemeth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan W. Baird
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cliona O’Farrelly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cliona O’Farrelly.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nemeth, E., Baird, A.W. & O’Farrelly, C. Microanatomy of the liver immune system. Semin Immunopathol 31, 333–343 (2009). https://doi.org/10.1007/s00281-009-0173-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-009-0173-4

Keywords

Search

Navigation