Title: Phenotypic and functional characterization of intrahepatic T lymphocytes during chronic hepatitis C
Abstract: HepatologyVolume 38, Issue 4 p. 829-841 Original ArticleFree Access Phenotypic and functional characterization of intrahepatic T lymphocytes during chronic hepatitis C Vincent Leroy, Vincent Leroy Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, France Department d'Hépato-Gastroentérologie, CHU de Grenoble, FranceSearch for more papers by this authorInes Vigan, Ines Vigan Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, FranceSearch for more papers by this authorJean-Francois Mosnier, Jean-Francois Mosnier Service d'Anatomie Pathologique, CHU de Nantes, FranceSearch for more papers by this authorTania Dufeu-Duchesne, Tania Dufeu-Duchesne Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, France Department d'Hépato-Gastroentérologie, CHU de Grenoble, FranceSearch for more papers by this authorMartine Pernollet, Martine Pernollet Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, FranceSearch for more papers by this authorJean-Pierre Zarski, Jean-Pierre Zarski Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, France Department d'Hépato-Gastroentérologie, CHU de Grenoble, FranceSearch for more papers by this authorPatrice N. Marche, Patrice N. Marche Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, FranceSearch for more papers by this authorEvelyne Jouvin-Marche, Corresponding Author Evelyne Jouvin-Marche [email protected] Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, FranceCEA-G/DRDC, INSERM U548, 17 rue des Martyrs, 38054 Grenoble Cedex 9, France. fax: (33) 438 7898 03===Search for more papers by this author Vincent Leroy, Vincent Leroy Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, France Department d'Hépato-Gastroentérologie, CHU de Grenoble, FranceSearch for more papers by this authorInes Vigan, Ines Vigan Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, FranceSearch for more papers by this authorJean-Francois Mosnier, Jean-Francois Mosnier Service d'Anatomie Pathologique, CHU de Nantes, FranceSearch for more papers by this authorTania Dufeu-Duchesne, Tania Dufeu-Duchesne Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, France Department d'Hépato-Gastroentérologie, CHU de Grenoble, FranceSearch for more papers by this authorMartine Pernollet, Martine Pernollet Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, FranceSearch for more papers by this authorJean-Pierre Zarski, Jean-Pierre Zarski Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, France Department d'Hépato-Gastroentérologie, CHU de Grenoble, FranceSearch for more papers by this authorPatrice N. Marche, Patrice N. Marche Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, FranceSearch for more papers by this authorEvelyne Jouvin-Marche, Corresponding Author Evelyne Jouvin-Marche [email protected] Laboratoire d'Immunochimie, CEA-G/DRDC, INSERM U548, Université Joseph-Fourier, Grenoble-I, FranceCEA-G/DRDC, INSERM U548, 17 rue des Martyrs, 38054 Grenoble Cedex 9, France. fax: (33) 438 7898 03===Search for more papers by this author First published: 07 March 2007 https://doi.org/10.1002/hep.1840380409Citations: 66AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract The pathogenesis of liver cell injury during chronic hepatitis C (CHC) is poorly understood. The cellular immune response is thought to play a key role in both inhibition of viral replication and liver pathology. However, little is currently known about which lymphocyte populations and which immune effectors contribute to or control liver damage. We investigated a panel of 15 phenotypic and functional markers of intrahepatic T-lymphocyte subsets irrespective of their antigen specificity in 48 hepatitis C virus (HCV)-infected patients and 8 healthy control subjects. Lymphocyte characteristics were evaluated from liver biopsy specimens both at gene expression level by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) and by immunochemistry, in relation with the degree of liver injury and with intrahepatic HCV-RNA levels. As compared with controls, we found major changes in T-lymphocyte subsets in HCV-infected patients, with a significant decrease of T-cell antigen receptor (TCR) δ and CD56 gene expression, associated with a concomitant increase of TCRα and CD8β that were correlated with cytotoxic factors, proinflammatory chemokines, and chemokine receptors including peforin, interferon gamma (IFN-γ), tumor necrosis factor α (TNF-α), RANTES, and CXCR3. The gene expression of CD8β, a specific marker for conventional TCRα+CD8+ lymphocytes, was correlated by multivariate analysis with both alanine aminotransferase (ALT) serum levels and histologic activity index. Furthermore, CD8 staining was observed by immunochemistry in the areas of lobular and piecemeal necrosis. In contrast, no lymphocyte marker was correlated with viral load, measured both in serum and in liver. In conclusion, these results strongly suggest key roles for CD8+ T cells as effectors of liver damage during chronic HCV infection and for their inability to control viral replication. (Hepatology 2003;38:829–841). References 1 Cooper S, Erickson AL, Adams EJ, Kansopon J, Weiner AJ, Chien DY, Houghton M, et al. Analysis of a successful immune response against hepatitis C virus. Immunity 1999; 10: 439– 449. 2 Gerlach JT, Diepolder HM, Jung MC., Gruener NH, Schraut WW, Zachoval R, Hoffmann R, et al. Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C [Comments]. Gastroenterology 1999; 117: 933– 941. 3 Gruner NH, Gerlach TJ, Jung MC., Diepolder HM, Schirren CA, Schraut WW, Hoffmann R, et al. Association of hepatitis C virus-specific CD8 + T cells with viral clearance in acute hepatitis C [In Process Citation]. J Infect Dis 2000; 181: 1528– 1536. 4 Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 2000; 191: 1499– 1512. 5 Thimme R, Oldach D, Chang KM, Steiger C., Ray SC., Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001; 194: 1395– 1406. 6 Erickson AL, Kimura Y, Igarashi S, Eichelberger J, Houghton M, Sidney J, McKinney D, et al. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 2001; 15: 883– 895. 7 Bain C., Fatmi A, Zoulim F, Zarski JP, Trepo C., Inchauspe G. Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection. Gastroenterology 2001; 120: 512– 524. 8 Crotta S, Stilla A, Wack A, D'Andrea A, Nuti S, D'Oro U, Mosca M, et al. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med 2002; 195: 35– 41. 9 Wong DK, Dudley DD, Afdhal NH, Dienstag J, Rice CM, Wang L, Houghton M, et al. Liver-derived CTL in hepatitis C virus infection: breadth and specificity of responses in a cohort of persons with chronic infection. J Immunol 1998; 160: 1479– 1488. 10 Schirren CA, Jung MC., Gerlach JT, Worzfeld T, Baretton G, Mamin M, Hubert Gruener N, et al. Liver-derived hepatitis C virus (HCV)-specific CD4(+) T cells recognize multiple HCV epitopes and produce interferon gamma. Hepatology 2000; 32: 597– 603. 11 Chang KM, Thimme R, Melpolder JJ, Oldach D, Pemberton J, Moorhead-Loudis J, McHutchison JG, et al. Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection. Hepatology 2001; 33: 267– 276. 12 Rosen HR, Miner C., Sasaki AW, Lewinsohn DM, Conrad AJ, Bakke A, Bouwer HG, et al. Frequencies of HCV-specific effector CD4+ T cells by flow cytometry: correlation with clinical disease stages. Hepatology 2002; 35: 190– 198. 13 Nuti S, Rosa D, Valiante NM, Saletti G, Caratozzolo M, Dellabona P, Barnaba V, et al. Dynamics of intra-hepatic lymphocytes in chronic hepatitis C: enrichment for Vα24+ T cells and rapid elimination of effector cells by apoptosis. Eur J Immunol 1998; 28: 3448– 3455. 14 Knodell RG, Ishak KG, Black WC., Chen TS, Craig R, Kaplowitz N, Kiernan TW, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1: 431– 435. 15 Mason DY, Sammons RE. The labeled antigen method of immunoenzymatic staining. J Histochem Cytochem 1979; 27: 832– 840. 16 Jouvin-Marche E, Vigan I, Leroy V, Marche PN. Quantitative RT-PCR for the detection of T cell receptor transcripts in T lymphocyte populations using the light cycler technology. In: MWC Meuer, KI Nakagawara. eds. Rapid Cycle Real-Time PCR: Methods and Applications. Berlin, Heidelberg, New York: Springer Verlag, 2000; 263– 271. 17 Deignan T, Curry MP, Doherty DG, Golden-Mason L, Volkov Y, Norris S, Nolan N, Traynor O, et al. Decrease in hepatic CD56(+) T cells and Vα24(+) natural killer T cells in chronic hepatitis C viral infection. J Hepatol 2002; 37: 101– 108. 18 Tran A, Yang G, Doglio A, Ticchioni M, Laffont C., Durant J, Bernard JL, et al. Phenotyping of intrahepatic and peripheral blood lymphocytes in patients with chronic hepatitis C. Dig Dis Sci 1997; 42: 2495– 2500. 19 Galle MB, DeFranco RM, Kerjaschki D, Romanelli RG, Montalto P, Gentilini P, Pinzani M, et al. Ordered array of dendritic cells and CD8+ lymphocytes in portal infiltrates in chronic hepatitis C. Histopathology 2001; 39: 373– 381. 20 Fiore G, Angarano I, Caccetta L, Serrone M, Jirillo E, Schiraldi O, Antonaci S. In situ immunophenotyping study of hepatic-infiltrating cytotoxic cells in chronic active hepatitis C. Eur J Gastroenterol Hepatol 1997; 9: 491– 496. 21 Curry MP, Norris S, Golden-Mason L, Doherty DG, Deignan T, Collins C., Traynor O, et al. Isolation of lymphocytes from normal adult human liver suitable for phenotypic and functional characterization. J Immunol Methods 2000; 242: 21– 31. 22 Ellmeier W, Sawada S, Littman DR. The regulation of CD4 and CD8 coreceptor gene expression during T cell development. Annu Rev Immunol 1999; 17: 523– 554. 23 Gao MH, Walz M, Kavathas PB. Post-transcriptional regulation associated with control of human CD8A expression of CD4+ T cells. Immunogenetics 1996; 45: 130– 135. 24 Paillard F, Sterkers G, Vaquero C. Transcriptional and post-transcriptional regulation of TcR, CD4 and CD8 gene expression during activation of normal human T lymphocytes. EMBO J 1990; 9: 1867– 1872. 25 Bernard K, Auphan N, Granjeaud S, Victorero G, Schmitt-Verhulst AM, Jordan BR, Nguyen C. Multiplex messenger assay: simultaneous, quantitative measurement of expression of many genes in the context of T-cell activation. Nucleic Acids Res 1996; 24: 1435– 1442. 26 Kawarabayashi N, Seki S, Hatsuse K, Ohkawa T, Koike Y, Aihara T, Habu Y, et al. Decrease of CD56(+) T cells and natural killer cells in cirrhotic livers with hepatitis C may be involved in their susceptibility to hepatocellular carcinoma. Hepatology 2000; 32: 962– 969. 27 Seki S, Habu Y, Kawamura T, Takeda K, Dobashi H, Ohkawa T, Hiraide H. The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T-helper 1 immune responses. Immunol Rev 2000; 174: 35– 46. 28 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: 921– 930. 29 Tseng CT, Klimpel GR. Binding of the hepatitis C virus envelope protein E2 to CD81 inhibits natural killer cell functions. J Exp Med 2002; 195: 43– 49. 30 Pernoller M, Jouvin-Marche E, Leroy V, Vigan I, Zarski JP, Marche P. Simultaneous evaluation of CD3+CD56+ T lymphocytes in the liver and in peripheral blood mononuclear cells of HCV-infected patients: correlation with severity of hepatic lesions. Clin Exp Immunol 2002; 130: 518– 525. 31 Salerno A, Dieli F. Role of γ δ T lymphocytes in immune response in humans and mice. Crit Rev Immunol 1998; 18: 327– 357. 32 Ferrick DA, Schrenzel MD, Mulvania T, Hsieh B, Ferlin WG, Lepper H. Differential production of interferon-gamma and interleukin-4 in response to Th1- and Th2-stimulating pathogens by gamma delta T cells in vivo. Nature 1995; 373: 255– 257. 33 Tseng CT, Miskovsky E, Houghton M, Klimpel GR. Characterization of liver T-cell receptor gammadelta T cells obtained from individuals chronically infected with hepatitis C virus (HCV): evidence for these T cells playing a role in the liver pathology associated with HCV infections. Hepatology 2001; 33: 1312– 1320. 34 Nelson DR, Marousis CG, Davis GL, Rice CM, Wong J, Houghton M, Lau JY. The role of hepatitis C virus-specific cytotoxic T lymphocytes in chronic hepatitis C. J Immunol 1997; 158: 1473– 1481. 35 He XS, Rehermann B, Lopez-Labrador FX, Boisvert J, Cheung R, Mumm J, Wedemeyer H, et al. Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers. Proc Natl Acad Sci U S A 1999; 96: 5692– 5697. 36 Grabowska AM, Lechner F, Klenerman P, Tighe PJ, Ryder S, Ball JK, Thomson BJ, et al. Direct ex vivo comparison of the breadth and specificity of the T cells in the liver and peripheral blood of patients with chronic HCV infection. Eur J Immunol 2001; 31: 2388– 2394. 37 Lechner F, Cuero AL, Kantzanou M, Klenerman P. Studies of human antiviral CD8+ lymphocytes using class I peptide tetramers. Rev Med Virol 2001; 11: 11– 22. 38 Sobao Y, Tomiyama H, Nakamura S, Sekihara H, Tanaka K, Takiguchi M. Visual demonstration of hepatitis C virus-specific memory CD8(+) T-cell expansion in patients with acute hepatitis C. Hepatology 2001; 33: 287– 294. 39 Toyonaga T, Hino O, Sugai S, Wakasugi S, Abe K, Shichiri M, Yamamura K. Chronic active hepatitis in transgenic mice expressing interferongamma in the liver. Proc Natl Acad Sci U S A 1994; 91: 614– 618. 40 Fukuda R, Ishimura N, Ishihara S, Chowdhury A, Morlyama N, Nogami C., Miyake T, et al. Intrahepatic expression of pro-inflammatory cytokine mRNAs and interferon efficacy in chronic hepatitis C. Liver 1996; 16: 390– 399. 41 Napoli J, Bishop GA, McGuinness PH, Painter DM, McCaughan GW. Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th 1-associated cytokines. Hepatology 1996; 24: 759– 765. 42 Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 1999; 163: 6236– 6243. 43 Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC., Lusso P. Identification of RANTES, MIP-1 α, and MIP-1 β as the major HIV- suppressive factors produced by CD8+ T cells. Science 1995; 270: 1811– 1815. 44 Kusano F, Tanaka Y, Marumo F, Sato C. Expression of C-C chemokines is associated with portal and periportal inflammation in the liver of patients with chronic hepatitis C. Lab Invest 2000; 80: 415– 422. 45 Di Martino V, Saurini F, Samuel D, Gigou M, Dussaix E, Reynes M, Bismuth H, et al. Long-term longitudinal study of intrahepatic hepatitis C virus replication after liver transplantation. Hepatology 1997; 26: 1343– 1350. 46 McHutchison JG, Poynard T, Esteban-Mur R, Davis GL, Goodman ZD, Harvey J, Ling MH, et al. Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin. Hepatology 2002; 35: 688– 693. 47 Negro F, Giostra E, Krawczynski K, Quadri R, Rubbia-Brandt L, Mentha G, Colucci G, et al. Detection of intrahepatic hepatitis C virus replication by strand-specific semi-quantitative RT-PCR: preliminary application to the liver transplantation model. J Hepatol 1998; 29: 1– 11. 48 Guidotti LG, Borrow P, Brown A, McClary H, Koch R, Chisari FV. Noncytopathic clearance of lymphocytic choriomeningitis virus from the hepatocyte. J Exp Med 1999; 189: 1555– 1564. 49 Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV. Viral clearance without destruction of infected cells during acute HBV infection. Science 1999; 284: 825– 829. 50 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. 51 Gruener NH, Lechner F, Jung MC., Diepolder H, Gerlach T, Lauer G, Walker B, et al. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Virol 2001; 75: 5550– 5558. 52 Wedemeyer H, He XS, Nascimbeni M, Davis AR, Greenberg HB, Hoofnagle JH, Liang TJ, et al. Impaired Effector Function of Hepatitis C Virus-Specific CD8(+) T Cells in Chronic Hepatitis C Virus Infection. J Immunol 2002; 169: 3447– 3458. Citing Literature Volume38, Issue4October 2003Pages 829-841 ReferencesRelatedInformation
Publication Year: 2003
Publication Date: 2003-10-01
Language: en
Type: article
Indexed In: ['crossref']
Access and Citation
Cited By Count: 79
AI Researcher Chatbot
Get quick answers to your questions about the article from our AI researcher chatbot