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http://dx.doi.org/10.4110/in.2010.10.4.120

T-Cell Dysfunction and Inhibitory Receptors in Hepatitis C Virus Infection  

Lee, Jino (Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST)
Suh, William I. (Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST)
Shin, Eui-Cheol (Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST)
Publication Information
IMMUNE NETWORK / v.10, no.4, 2010 , pp. 120-125 More about this Journal
Abstract
Dysfunction of the virus-specific T cells is a cardinal feature in chronic persistent viral infections such as one caused by hepatitis C virus (HCV). In chronic HCV infection, virus-specific dysfunctional CD8 T cells often overexpress various inhibitory receptors. Programmed cell death 1 (PD-1) was the first among these inhibitory receptors that were identified to be overexpressed in functionally impaired T cells. The roles of other inhibitory receptors such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) have also been demonstrated in T-cell dysfunctions that occur in chronic HCV patients. Blocking these inhibitory receptors in vitro restores the functions of HCV-specific CD8 T cells and allows enhanced proliferation, cytolytic activity and cytokine production. Therefore, the blockade of the inhibitory receptors is considered as a novel strategy for the treatment of chronic HCV infection.
Keywords
Hepatitis C virus; CD8 T cells; T-cell dysfunction; PD-1; CTLA-4; Tim-3;
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1 Shepard CW, Finelli L, Alter MJ: Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 5;558-567, 2005   DOI   ScienceOn
2 Kamal SM: Acute hepatitis C: a systematic review. Am J Gastroenterol 103;1283-1297, 2008   DOI   ScienceOn
3 Alter HJ, Seeff LB: Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome. Semin Liver Dis 20;17-35, 2000   DOI   ScienceOn
4 Diepolder HM, Zachoval R, Hoffmann RM, Wierenga EA, Santantonio T, Jung MC, Eichenlaub D, Pape GR: Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 346;1006-1007, 1995   DOI   ScienceOn
5 Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT, Dohrenwend P, Robbins G, Phillips R, Klenerman P, Walker BD: Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191;1499-1512, 2000   DOI   ScienceOn
6 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 194;1395-1406, 2001   DOI   ScienceOn
7 Cooper S, Erickson AL, Adams EJ, Kansopon J, Weiner AJ, Chien DY, Houghton M, Parham P, Walker CM: Analysis of a successful immune response against hepatitis C virus. Immunity 10;439-449, 1999   DOI   ScienceOn
8 Thimme R, Bukh J, Spangenberg HC, Wieland S, Pemberton J, Steiger C, Govindarajan S, Purcell RH, Chisari FV: Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci USA 99;15661-15668, 2002   DOI   ScienceOn
9 Rehermann B, Nascimbeni M: Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 5;215-229, 2005   DOI   ScienceOn
10 Dustin LB, Rice CM: Flying under the radar: the immunobiology of hepatitis C. Annu Rev Immunol 25;71-99, 2007   DOI   ScienceOn
11 Erickson AL, Kimura Y, Igarashi S, Eichelberger J, Houghton M, Sidney J, McKinney D, Sette A, Hughes AL, Walker CM: The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 15;883-895, 2001   DOI   ScienceOn
12 Chang KM, Rehermann B, McHutchison JG, Pasquinelli C, Southwood S, Sette A, Chisari FV: Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus. J Clin Invest 100;2376-2385, 1997   DOI   ScienceOn
13 Weiner A, Erickson AL, Kansopon J, Crawford K, Muchmore E, Hughes AL, Houghton M, Walker CM: Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant. Proc Natl Acad Sci USA 92;2755-2759, 1995   DOI   ScienceOn
14 Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, Ogg GS, King A, Lechner F, Spina CA, Little S, Havlir DV, Richman DD, Gruener N, Pape G, Waters A, Easterbrook P, Salio M, Cerundolo V, McMichael AJ, Rowland-Jones SL: Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8;379-385, 2002   DOI   ScienceOn
15 Sugimoto K, Ikeda F, Stadanlick J, Nunes FA, Alter HJ, Chang KM: Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology 38;1437-1448, 2003
16 Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ: The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8;239-245, 2007   DOI   ScienceOn
17 Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R: Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439;682-687, 2006   DOI   ScienceOn
18 Radziewicz H, Ibegbu CC, Fernandez ML, Workowski KA, Obideen K, Wehbi M, Hanson HL, Steinberg JP, Masopust D, Wherry EJ, Altman JD, Rouse BT, Freeman GJ, Ahmed R, Grakoui A: Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol 81;2545-2553, 2007   DOI   ScienceOn
19 Penna A, Pilli M, Zerbini A, Orlandini A, Mezzadri S, Sacchelli L, Missale G, Ferrari C: Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 45;588-601, 2007   DOI   ScienceOn
20 Golden-Mason L, Palmer B, Klarquist J, Mengshol JA, Castelblanco N, Rosen HR: Upregulation of PD-1 expression on circulating and intrahepatic hepatitis C virus- specific CD8+ T cells associated with reversible immune dysfunction. J Virol 81:9249-9258, 2007   DOI   ScienceOn
21 Radziewicz H, Ibegbu CC, Hon H, Osborn MK, Obideen K, Wehbi M, Freeman GJ, Lennox JL, Workowski KA, Hanson HL, Grakoui A: Impaired hepatitis C virus (HCV)-specific effector CD8+ T cells undergo massive apoptosis in the peripheral blood during acute HCV infection and in the liver during the chronic phase of infection. J Virol 82;9808-9822, 2008   DOI   ScienceOn
22 Nakamoto N, Kaplan DE, Coleclough J, Li Y, Valiga ME, Kaminski M, Shaked A, Olthoff K, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang KM: Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 134;1927-1937, 2008   DOI   ScienceOn
23 Rutebemberwa A, Ray SC, Astemborski J, Levine J, Liu L, Dowd KA, Clute S, Wang C, Korman A, Sette A, Sidney J, Pardoll DM, Cox AL: High-programmed death-1 levels on hepatitis C virus-specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection. J Immunol 181;8215-8225, 2008   DOI
24 Folgori A, Capone S, Ruggeri L, Meola A, Sporeno E, Ercole BB, Pezzanera M, Tafi R, Arcuri M, Fattori E, Lahm A, Luzzago A, Vitelli A, Colloca S, Cortese R, Nicosia A: A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat Med 12; 190-197, 2006   DOI   ScienceOn
25 Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, Missale G, Ferrari C: PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 80;11398-11403, 2006   DOI   ScienceOn
26 Kasprowicz V, Schulze Zur Wiesch J, Kuntzen T, Nolan BE, Longworth S, Berical A, Blum J, McMahon C, Reyor LL, Elias N, Kwok WW, McGovern BG, Freeman G, Chung RT, Klenerman P, Lewis-Ximenez L, Walker BD, Allen TM, Kim AY, Lauer GM: High level of PD-1 expression on hepatitis C virus (HCV)-specific CD8+ and CD4+ T cells during acute HCV infection, irrespective of clinical outcome. J Virol 82;3154-3160, 2008   DOI   ScienceOn
27 Rollier CS, Paranhos-Baccala G, Verschoor EJ, Verstrepen BE, Drexhage JA, Fagrouch Z, Berland JL, Komurian-Pradel F, Duverger B, Himoudi N, Staib C, Meyr M, Whelan M, Whelan JA, Adams VC, Larrea E, Riezu JI, Lasarte JJ, Bartosch B, Cosset FL, Spaan WJ, Diepolder HM, Pape GR, Sutter G, Inchauspe G, Heeney JL: Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity. Hepatology 45;602-613, 2007   DOI   ScienceOn
28 Chambers CA, Kuhns MS, Egen JG, Allison JP: CTLA-4- mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19;565-594, 2001   DOI   ScienceOn
29 Nakamoto N, Cho H, Shaked A, Olthoff K, Valiga ME, Kaminski M, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang KM: Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog 5;e1000313, 2009   DOI   ScienceOn
30 Meyers JH, Sabatos CA, Chakravarti S, Kuchroo VK: The TIM gene family regulates autoimmune and allergic diseases. Trends Mol Med 11;362-369, 2005   DOI   ScienceOn
31 Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DA, Wherry EJ: Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10;29-37, 2009   DOI   ScienceOn
32 Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, Wong JC, Satkunarajah M, Schweneker M, Chapman JM, Gyenes G, Vali B, Hyrcza MD, Yue FY, Kovacs C, Sassi A, Loutfy M, Halpenny R, Persad D, Spotts G, Hecht FM, Chun TW, McCune JM, Kaul R, Rini JM, Nixon DF, Ostrowski MA: Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med 205;2763-2779, 2008   DOI   ScienceOn
33 Vali B, Jones RB, Sakhdari A, Sheth PM, Clayton K, Yue FY, Gyenes G, Wong D, Klein MB, Saeed S, Benko E, Kovacs C, Kaul R, Ostrowski MA: HCV-specific T cells in HCV/HIV co-infection show elevated frequencies of dual Tim-3/PD-1 expression that correlate with liver disease progression. Eur J Immunol 40;2493-2505, 2010   DOI   ScienceOn
34 Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber DL, Ahmed R: Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27;670-684, 2007   DOI   ScienceOn
35 Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M, Blum HE, Pircher H, Thimme R: Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog 6;e1000947, 2010   DOI   ScienceOn
36 Chang DY, Shin EC: Immune-based therapy for chronic hepatitis C. J Leukoc Biol 86;33-39, 2009   DOI   ScienceOn
37 Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, Vanderford TH, Chennareddi L, Silvestri G, Freeman GJ, Ahmed R, Amara RR: Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458;206-210, 2009   DOI   ScienceOn
38 Golden-Mason L, Palmer BE, Kassam N, Townshend- Bulson L, Livingston S, McMahon BJ, Castelblanco N, Kuchroo V, Gretch DR, Rosen HR: Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol 83;9122-9130, 2009   DOI   ScienceOn
39 Shin EC, Rehermann B: Taking the brake off T cells in chronic viral infection. Nat Med 12;276-277, 2006   DOI   ScienceOn