The Activation of HCV-specific CD8 T Cells by HCV Peptide Pulsed Huh7.5 Cells

Huh7.5 간암 세포주의 HCV 항원제시에 의한 HCV 특이 T 림프구의 활성에 관한 연구

  • Cho, Hyo-Sun (Department of Pharmacy, Duksung Women's University)
  • 조효선 (덕성여자대학교 약학대학 약학과)
  • Received : 2011.11.15
  • Accepted : 2011.12.10
  • Published : 2011.12.31

Abstract

T cells play a key role in viral infection. However, in patients with chronic hepatitis C virus (HCV) infection, HCV-specific T cells are dysfunctional and impaired in the liver, which is the primary site for HCV replication. There are multiple potential mechanisms for HCV-specific T cell dysfunction including induction of immune inhibitory pathways (program death-1; PD-1, cytotoxic t lymphocyte associated antigen-4; CTLA-4) and immune tolerance induced specific for the liver. However, the interaction between hepatocytes and HCV-specific CD8 T cells has not clearly established. In this study, we confirmed huh (human hepatoma) 7.5 cells expressing HLA (human leukocyte antigen) A2 presented antigen to activate HCV-specific CD8 T cells in HLA A2-restricted manner and expression of PD-L (program death ligand) 1 on huh7.5 cells reduced HCV-specific CD8 T cell activation, suggesting an immune modulatory activity. Loss of HCV-specific tetramer responses following antigenic stimulation correlated with increased caspase-3 activity. In addition, PD-L1 on huh7.5 cells rescued HCV-specific CD8 T cells from apoptosis. Our results suggest that the interaction between PD-L1 and PD-1 can recover the function of HCV-specific CD8 T cells in the liver, which could be applied in therapy of HCV chronic infection.

References

  1. Bertolino, P., G.W. McCaughan, and D.G. Bowen. 2002. Role of primary intrahepatic T-cell activation in the 'liver tolerance effect'. Immunol. Cell. Biol. 80, 84-92. https://doi.org/10.1046/j.0818-9641.2001.01048.x
  2. Binder, M., G. Kochs, R. Bartenschlager, and V. Lohmann. 2007. Hepatitis C virus escape from the interferon regulatory factor 3 pathway by a passive and active evasion strategy. Hepatology 46, 1365-1374. https://doi.org/10.1002/hep.21829
  3. Chayama, K., C.N. Hayes, N. Hiraga, H. Abe, M. Tsuge, and M. Imamura. 2011. Animal model for study of human hepatitis viruses. J. Gastroenterol. Hepatol. 26, 13-18. https://doi.org/10.1111/j.1440-1746.2010.06470.x
  4. Freeman, G.J., A.J. Long, and Y. Iwai. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027-1034. https://doi.org/10.1084/jem.192.7.1027
  5. Freeman, G.J., E.J. Wherry, R. Ahmed, and A.H. Sharpe. 2006. Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J. Exp. Med. 203, 2223-2227. https://doi.org/10.1084/jem.20061800
  6. Golden-Mason, L., B. Palmer, J. Klarquist, J.A. Mengshol, and N. Castelblanco. 2007. 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. https://doi.org/10.1128/JVI.00409-07
  7. Greenwald, R.J., G.J. Freeman, and A.H. Sharpe. 2005. The B7 family revisited. Annu. Rev. Immunol. 23, 515-548. https://doi.org/10.1146/annurev.immunol.23.021704.115611
  8. Holz, L.E., A. Warren, D.G. Le Couteur, D.G. Bowen, and P. Bertolino. 2010. CD8+ T cell tolerance following antigen recognition on hepatocytes. J. Autoimmun. 34, 15-22. https://doi.org/10.1016/j.jaut.2009.08.005
  9. Jo, J., U. Aichele, N. Kersting, R. Klein, P. Aichele, E. Bisse, A.K. Sewell, H.E. Blum, R. Bartenschlager, V. Lohmann, and R. Thimme. 2009. Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication using a novel immunological model. Gastroenterology 136, 1391-1401. https://doi.org/10.1053/j.gastro.2008.12.034
  10. Jo, J., V. Lohmann, R. Bartenschlager, and R. Thimme. 2011. Experimental models to study the immunobiology of hepatitis C virus. J. Gen. Virol. 92, 477-493. https://doi.org/10.1099/vir.0.027987-0
  11. Keril, J.B., A.J. McKeating, and M.C. Rice, 2002. Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J. Virol. 76, 13001-13014. https://doi.org/10.1128/JVI.76.24.13001-13014.2002
  12. Lauer, G.M. and B.D. Walker. 2001. Hepatitis C virus infection. New Engl. J. Med. 345, 41-52. https://doi.org/10.1056/NEJM200107053450107
  13. Nakamoto, N., D.E. Kaplan, J. Coleclough, Y. Li, M.E. Valiga, and K.M. Chang. 2008. Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 134, 1927-1937. https://doi.org/10.1053/j.gastro.2008.02.033
  14. Nakamoto, N., H. Cho, A. Shaked, K. Olthoff, M.E. Valiga, M. Kaminski, E. Gostick, D.A. Price, G.J. Freeman, E.J. Wherry, and K.M. Chang. 2009. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog. 5, e1000313. https://doi.org/10.1371/journal.ppat.1000313
  15. Pagliaro, L., A. Craxi, C. Cammaa, F. Tine, V. di Marco, L. Iacono, and P. Almasio. 1994. Interferon-alpha for chronic hepatitis C: an analysis of pretreatment clinical predictors of response. Hepatology 19, 820-828.
  16. Salomon, B. and J.A. Bluestone. 2001. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu. Rev. Immunol. 19, 225-252. https://doi.org/10.1146/annurev.immunol.19.1.225
  17. Uebelhoer, L., J.H. Han, B. Callendret, G. Mateu, N.H. Shoukry, H.L. Hanson, C.M. Rice, C.M. Walker, and A. Grakoui. 2008. Stable cytotoxic T cell escape mutation in hepatitis C virus is linked to maintenance of viral fitness. PLoS Pathog. 4, e1000143. https://doi.org/10.1371/journal.ppat.1000143
  18. Varela-Rohena, A., C. Carpenito, E.E. Perez, M. Richardson, R.V. Parry, M. Milone, J. Scholler, X. Hao, A. Mexas, R.G. Carroll, C.H. June, and J.L. Riley. 2008. Genetic engineering of T cells for adoptive immunotherapy. Immunol. Res. 42, 166-181. https://doi.org/10.1007/s12026-008-8057-6
  19. Wherry, E.J. and R. Ahmed. 2004. Memory CD8 T-cell differentiation during viral infection. J. Virol. 8, 5535-5545.
  20. Willberg, C., E. Barnes, and P. Klenerman. 2003. HCV immunology-death and the maiden T cell. Cell. Death Differ. 10, S39-47. https://doi.org/10.1038/sj.cdd.4401122