Abstract
Whereas innate immunity can provide the initial defense against infections, completely effective immunity to an invading microbial organism typically requires an adaptive immune response specific to the invader. Adaptive immune responses in the liver contribute both to effective defense against invading microbes and to a variety of pathologic states. The term adaptive immunity refers to lymphocyte-mediated immune defense tailored to a specific microbial invader. Adaptive immunity can be classified into humoral immunity and cell-mediated immunity, mediated principally by B and T lymphocytes, respectively. Antigens are structures found on microbes that are recognized as foreign by B or T lymphocytes. Antigens elicit specific responses from the lymphocytes expressing cognate antigen receptors. Such specific responses include both clonal proliferation and lymphocyte differentiation into specialized effector cell types with important functions serving to fight microbes. Such functions include the release of antibody (B cells), the killing of infected cells (cytotoxic T cells), and extracellular release of signaling molecules (i.e., cytokines) that can act in an autocrine, paracrine, or endocrine fashion to elicit responses from other immune and nonimmune cells.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Doherty DG, O’Farrelly C. Innate and adaptive lymphoid cells in the human liver. Immunol Rev 2000; 174:5–20.
Huang L. T cells expressing alpha beta antigen receptors in the liver. In: Crispe IN, ed. T Lymphocytes in the Liver: Immunobiology, Pathology, and Host Defense. New York: Wiley-Liss; 1999:15–39.
Reinhardt RL, Khoruts A, Merica R, Zell T, Jenkins MK. Visualizing the generation of memory CD4 T cells in the whole body. Nature 2001; 410:101–105.
Mehal WZ, Juedes AE, Crispe IN. Selective retention of activated CD8+ T cells by the normal liver. J Immunol 1999; 163: 3202–3210.
Park S, Murray D, John B, Crispe IN. Biology and significance of T-cell apoptosis in the liver. Immunol Cell Biol 2002; 80:74–83.
Swain SL Regulation of the generation and maintenance of T-cell memory: a direct, default pathway from effectors to memory cells. Microbes Infect 2003; 5:213–219.
Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol 2002; 2:933–944.
Lan RY, Ansari AA, Lian ZX, Gershwin ME. Regulatory T cells: development, function and role in autoimmunity. Autoimmun Rev 2005; 4:351–363.
Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity 2004; 21:467–476.
Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201:233–240.
Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25naïve T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198:1875–1886.
Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006; 24:179–189.
Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441:235–238.
Hussain MJ, Mustafa A, Gallati H, Mowat AP, Mieli-Vergani G, Vergani D. Cellular expression of tumour necrosis factor-alpha and interferon-gamma in the liver biopsies of children with chronic liver disease. J Hepatol 1994; 21:816–821.
Lohr HF, Schlaak JF, Gerken G, Fleischer B, Dienes HP, Meyer Zum Buschenfelde KH. Phenotypical analysis and cytokine release of liver-infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology. Liver 1994; 14:161–166.
Lohr HF, Schlaak JF, Lohse AW, et al. Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibodypositive autoimmune hepatitis. Hepatology 1996; 24:1416–1421.
Gantner F, Leist M, Lohse AW, Germann PG, Tiegs G. Concanavalin A-induced T-cell-mediated hepatic injury in mice: the role of tumor necrosis factor. Hepatology 1995; 21:190–198.
Leist M, Gantner F, Jilg S, Wendel A. Activation of the 55 kDa TNF receptor is necessary and sufficient for TNF-induced liver failure, hepatocyte apoptosis, and nitrite release. J Immunol 1995; 154: 1307–1316.
Bird GL, Sheron N, Goka AK, Alexander GJ, Williams RS. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann Intern Med 1990; 112:917–920.
Larrea E, Garcia N, Qian C, Civeira MP, Prieto J. Tumor necrosis factor alpha gene expression and the response to interferon in chronic hepatitis C. Hepatology 1996; 23:210–217.
Grivennikov SI, Tumanov AV, Liepinsh DJ, et al. Distinct and nonredundant in vivo functions of TNF produced by T cells and macrophages/ neutrophils: protective and deleterious effects. Immunity 2005; 22:93–104.
Bradham CA, Plumpe J, Manns MP, Brenner DA, Trautwein C. Mechanisms of hepatic toxicity. I. TNF-induced liver injury. Am J Physiol 1998; 275:G387–G392.
Toyonaga T, Hino O, Sugai S, et al. Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver. Proc Natl Acad Sci USA 1994; 91:614–618.
Alexander WS, Starr R, Fenner JE, et al. SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 1999; 98: 597–608.
Lin JT, Martin SL, Xia L, Gorham JD. TGF-beta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet. J Immunol 2005; 174:5950–5958.
Gorelik L, Constant S, Flavell RA. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentia-4 tion. J Exp Med 2002; 195:1499–1505.
Rudner LA, Lin JT, Park IK, et al. Necroinflammatory liver disease in BALB/c background, TGF-beta 1-deficient mice requires CD4+ T cells. J Immunol 2003; 170:4785–4792.
Gorham JD, Lin JT, Sung JL, Rudner LA, French MA. Genetic regulation of autoimmune disease: BALB/c background TGF-beta 1-deficient mice develop necroinflammatory IFN-gamma-dependent hepatitis. J Immunol 2001; 166:6413–6422.
Pearce EJ, Caspar P, Grzych JM, Lewis FA, Sher A. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med 1991; 173:159–166.
Wynn TA, Thompson RW, Cheever AW, Mentink-Kane MM. Immunopathogenesis of schistosomiasis. Immunol Rev 2004; 201: 156–167.
Fallon PG, Richardson EJ, McKenzie GJ, McKenzie AN. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J Immunol 2000; 164:2585–2591.
Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J Clin Invest 1999; 104:777–785.
Toyabe S, Seki S, Iiai T, et al. Requirement of IL-4 and liver NK1+ T cells for concanavalin A-induced hepatic injury in mice. J Immunol 1997; 159:1537–1542.
Kaneko Y, Harada M, Kawano T, et al. Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis. J Exp Med 2000; 191:105–114.
Jaruga B, Hong F, Sun R, Radaeva S, Gao B. Crucial role of IL-4/ STAT6 in T cell-mediated hepatitis: up-regulating eotaxins and IL-5 and recruiting leukocytes. J Immunol 2003; 171:3233–3244.
Louis H, LeMoine A, Flamand V, et al. Critical role of interleukin 5 and eosinophils in concanavalin A-induced hepatitis in mice. Gastroenterology 2002; 122:2001–2010.
Bach JF Regulatory T cells under scrutiny. Nat Rev Immunol 2003; 3:189–198.
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of selftolerance causes various autoimmune diseases. J Immunol 1995; 155:1151–1164.
Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001; 27:68–73.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4:330–336.
Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 2005; 6:331–337.
Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25-T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 2004; 172:5149–5153.
Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol 2004; 41:31–37.
Lan RY, Cheng C, Lian ZX, et al. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 2006; 43:729–737.
Longhi MS, Hussain MJ, Mitry RR, et al. Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol 2006; 176:4484–4491.
Longhi MS, Ma Y, Mitry RR, et al. Effect of CD4+ CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis. J Autoimmun 2005; 25:63–71.
Unitt E, Rushbrook SM, Marshall A, et al. Compromised lympho-4 cytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 2005; 41:722–730.
Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 2005; 65:2457–2464.
Yang XH, Yamagiwa S, Ichida T, et al. Increase of CD4(+)CD25(+) regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol 2006; 45:254–262.
Cabrera R, Tu Z, Xu Y, et al. An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology 2004; 40:1062–1071.
Boettler T, Spangenberg HC, Neumann-Haefelin C, et al. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro prolifer-4 ation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol 2005; 79:7860–7867.
Rushbrook SM, Ward SM, Unitt E, et al. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J Virol 2005; 79:7852–7859.
Bolacchi F, Sinistro A, Ciaprini C, et al. Increased hepatitis C virus (HCV)-specific CD4+CD25+ regulatory T lymphocytes and reduced HCV-specific CD4+ T cell response in HCV-infected patients with normal versus abnormal alanine aminotransferase levels. Clin Exp Immunol 2006; 144:188–196.
Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest 2006; 116:1218–1222.
Witowski J, Ksiazek K, Jorres A. Interleukin-17: a mediator of inflammatory responses. Cell Mol Life Sci 2004; 61:567–579.
Mangan PR, Harrington LE, O’Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006; 441:231–234.
Kleinschek MA, Muller U, Brodie SJ, et al. IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12. J Immunol 2006; 176:1098–1106.
Wiekowski MT, Leach MW, Evans EW, et al. Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J Immunol 2001; 166: 7563–7570.
Caldwell CC, Okaya T, Martignoni A, Husted T, Schuster R, Lentsch AB. Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol 2005; 289:G969–976.
Exley MA, Koziel MJ. To be or not to be NKT: natural killer T cells in the liver. Hepatology 2004; 40:1033–1040.
Zhou D, Mattner J, Cantu C, 3rd, et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 2004; 306:1786–1789.
Mattner J, Debord KL, Ismail N, et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 2005; 434:525–529.
Kinjo Y, Wu D, Kim G, et al. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 2005; 434:520–525.
Godfrey DI, Kronenberg M. Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 2004; 114:1379–1388.
Osman Y, Kawamura T, Naito T, et al. Activation of hepatic NKT cells and subsequent liver injury following administration of alphagalactosylceramide. Eur J Immunol 2000; 30:1919–1928.
Takeda K, Hayakawa Y, VanKaer L, Matsuda H, Yagita H, Okumura K. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci USA 2000; 97:5498–5503.
Kita H, Naidenko OV, Kronenberg M, et al. Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology 2002; 123: 1031–1043.
Thimme R, Bukh J, Spangenberg HC, et al. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci USA 2002; 99:15,661–15,668.
Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 1996; 4:25–36.
Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology 2006; 43 (2 Suppl 1):S54–62.
Hata K, Zhang XR, Iwatsuki S, VanThiel DH, Herberman RB, Whiteside TL. Isolation, phenotyping, and functional analysis of lymphocytes from human liver. Clin Immunol Immunopathol 1990; 56:401–419.
Smith F, Golden-Mason L, Deignan T, et al. Localization of T and B lymphocytes in histologically normal adult human donor liver. Hepatogastroenterology 2003; 50:1311–1315.
Racanelli V, Sansonno D, Piccoli C, D’Amore FP, Tucci FA, Dammacco F Molecular characterization of B cell clonal expan-4 sions in the liver of chronically hepatitis C virus-infected patients. J Immunol 2001; 167:21–29.
Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006; 354:54–66.
Strassburg CP, Manns MP Autoantibodies and autoantigens in autoimmune hepatitis. Semin Liver Dis 2002; 22:339–352.
Kubes P, Kanwar S. Histamine induces leukocyte rolling in postcapillary venules. A P-selectin-mediated event. J Immunol 1994; 152:3570–3577.
Mayadas TN, Johnson RC, Rayburn H, Hynes RO, Wagner DD. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 1993; 74:541–554.
Ley K, Bullard DC, Arbones ML, et al. Sequential contribution of L-and P-selectin to leukocyte rolling in vivo. J Exp Med 1995; 181:669–675.
Steinhoff G, Behrend M, Schrader B, Duijvestijn AM, Wonigeit K Expression patterns of leukocyte adhesion ligand molecules on human liver endothelia. Lack of ELAM-1 and CD62 inducibility on sinusoidal endothelia and distinct distribution of VCAM-1, ICAM-1, ICAM-2, and LFA-3. Am J Pathol 1993; 142:481–488.
Lalor PF, Shields P, Grant A, Adams DH. Recruitment of lymphocytes to the human liver. Immunol Cell Biol 2002; 80:52–64.
Hamann A, Klugewitz K, Austrup F, Jablonski-Westrich D. Activation induces rapid and profound alterations in the trafficking of T cells. Eur J Immunol 2000; 30:3207–3218.
John B, Crispe IN. Passive and active mechanisms trap activated CD8+ T cells in the liver. J Immunol 2004; 172:5222–5229.
Bonder CS, Norman MU, Swain MG, et al. Rules of recruitment for Th1 and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and vascular adhesion protein-1. Immunity 2005; 23: 153–163.
Geissmann F, Cameron TO, Sidobre S, et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol 2005; 3:e113.
Huang L, Soldevila G, Leeker M, Flavell R, Crispe IN. The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo. Immunity 1994; 1:741–749.
Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP. The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev 2000; 174:47–62.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Humana Press Inc., Totowa, NJ
About this chapter
Cite this chapter
Gorham, J.D. (2007). Adaptive Immunity in the Liver. In: Gershwin, M.E., Vierling, J.M., Manns, M.P. (eds) Liver Immunology. Humana Press. https://doi.org/10.1007/978-1-59745-518-3_6
Download citation
DOI: https://doi.org/10.1007/978-1-59745-518-3_6
Publisher Name: Humana Press
Print ISBN: 978-1-58829-818-8
Online ISBN: 978-1-59745-518-3
eBook Packages: MedicineMedicine (R0)