Abstract
Interleukin-21 (IL-21)+CD4+ T cells are involved in the immune response against hepatitis B virus (HBV) by secreting IL-21. However, the role of IL-21+CD4+ T cells in the immune response against chronic hepatitis C (CHC) virus infection is poorly understood. This study aimed to investigate the role of IL-21+CD4+ T cells in CHC patients and the potential mechanisms. The study subjects included nineteen CHC patients who were grouped by viral load (low, < 106 RNA copies/ml, n = 8; high, > 106 RNA copies/ml, n = 11). The peripheral frequency of HCV-specific IL-21+CD4+ T cells was higher in the low viral load group and was negatively correlated with the serum HCV RNA viral load in all CHC patients. Meanwhile, IL-21+ cells accumulated in the liver in the low viral load group. In vitro, IL-21 treatment increased the expression of proliferation markers and cytolytic molecules on HCV-specific CD8+ T cells. In summary, these findings suggest that HCV-specific IL-21+CD4+ T cells might contribute to HCV control by rescuing HCV-specific CD8+ T cells in CHC patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Betts, M.R., Casazza, J.P., Patterson, B.A., Waldrop, S., Trigona, W., Fu, T.M., Kern, F., Picker, L.J., and Koup, R.A. (2000). Putative immunodominant human immunodeficiency virus-specific CD8(+) T-cell responses cannot be predicted by major histocompatibility complex class I haplotype. J. Virol. 74, 9144–9151.
Blackburn, S.D., Shin, H., Haining, W.N., Zou, T., Workman, C.J., Polley, A., Betts, M.R., Freeman, G.J., Vignali, D.A., and Wherry, E.J. (2009). Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37.
Elsaesser, H., Sauer, K., and Brooks, D.G. (2009). IL-21 is required to control chronic viral infection. Science 324, 1569–1572.
Fazilleau, N., Mark, L., McHeyzer-Williams, L.J., and McHeyzer-Williams, M.G. (2009). Follicular helper T cells: lineage and location. Immunity 30, 324–335.
Fu, J., Xu, D., Liu, Z., Shi, M., Zhao, P., Fu, B., Zhang, Z., Yang, H., Zhang, H., Zhou, C., et al. (2007). Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132, 2328–2339.
Gallimore, A., Glithero, A., Godkin, A., Tissot, A.C., Pluckthun, A., Elliott, T., Hengartner, H., and Zinkernagel, R. (1998). Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J. Exp. Med. 187, 1383–1393.
Golden-Mason, L., Palmer, B.E., Kassam, N., Townshend-Bulson, L., Livingston, S., McMahon, B.J., Castelblanco, N., Kuchroo, V., Gretch, D.R., and Rosen, H.R. (2009). 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.
Gruener, N.H., Lechner, F., Jung, M.C., Diepolder, H., Gerlach, T., Lauer, G., Walker, B., Sullivan, J., Phillips, R., Pape, G.R., et al. (2001). Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J. Virol. 75, 5550–5558.
Iannello, A., Boulassel, M.R., Samarani, S., Debbeche, O., Tremblay, C., Toma, E., Routy, J.P., and Ahmad, A. (2010). Dynamics and consequences of IL-21 production in HIV-infected individuals: a longitudinal and cross-sectional study. J. Immunol. 184, 114–126.
Korn, T., Bettelli, E., Gao, W., Awasthi, A., Jager, A., Strom, T.B., Oukka, M., and Kuchroo, V.K. (2007). IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448, 484–487.
Lavanchy, D. (2011). Evolving epidemiology of hepatitis C virus. Clin. Microbiol. Infect. 17, 107–115.
Leroux-Roels, G., Esquivel, C.A., DeLeys, R., Stuyver, L., Elewaut, A., Philippe, J., Desombere, I., Paradijs, J., and Maertens, G. (1996). Lymphoproliferative responses to hepatitis C virus core, E1, E2, and NS3 in patients with chronic hepatitis C infection treated with interferon alfa. Hepatology 23, 8–16.
McMahan, R.H., Golden-Mason, L., Nishimura, M.I., McMahon, B.J., Kemper, M., Allen, T.M., Gretch, D.R., and Rosen, H.R. (2010). Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J. Clin. Invest. 120, 4546–4557.
Mehta, D.S., Wurster, A.L., and Grusby, M.J. (2004). Biology of IL-21 and the IL-21 receptor. Immunol. Rev. 202, 84–95.
Mosmann, T.R., and Sad, S. (1996). The expanding universe of Tcell subsets: Th1, Th2 and more. Immunol. Today 17, 138–146.
Neumann-Haefelin, C., and Thimme, R. (2013). Adaptive immune responses in hepatitis C virus infection. Curr. Top. Microbiol. Immunol. 369, 243–262.
Ou, R., Zhou, S., Huang, L., and Moskophidis, D. (2001). Critical role for alpha/beta and gamma interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells. J. Virol. 75, 8407–8423.
Ozaki, K., Spolski, R., Feng, C.G., Qi, C.F., Cheng, J., Sher, A., Morse, H.R., Liu, C., Schwartzberg, P.L., and Leonard, W.J. (2002). A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634.
Publicover, J., Goodsell, A., Nishimura, S., Vilarinho, S., Wang, Z.E., Avanesyan, L., Spolski, R., Leonard, W.J., Cooper, S., and Baron, J.L. (2011). IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J. Clin. Invest. 121, 1154–1162.
Radziewicz, H., Ibegbu, C.C., Hon, H., Osborn, M.K., Obideen, K., Wehbi, M., Freeman, G.J., Lennox, J.L., Workowski, K.A., Hanson, H.L., et al. (2008). 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.
Shepard, C.W., Finelli, L., and Alter, M.J. (2005). Global epidemiology of hepatitis C virus infection. Lancet Infect. Dis. 5, 558–567.
Spolski, R., and Leonard, W.J. (2008). Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol. 26, 57–79.
Sun, J.C., and Bevan, M.J. (2003). Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342.
Sun, J.C., Williams, M.A., and Bevan, M.J. (2004). CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat. Immunol. 5, 927–933.
Wang, G., Tschoi, M., Spolski, R., Lou, Y., Ozaki, K., Feng, C., Kim, G., Leonard, W.J., and Hwu, P. (2003). In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res. 63, 9016–9022.
Wedemeyer, H., He, X.S., Nascimbeni, M., Davis, A.R., Greenberg, H.B., Hoofnagle, J.H., Liang, T.J., Alter, H., and Rehermann, B. (2002). Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J. Immunol. 169, 3447–3458.
Yang, S.H., Lee, C.G., Lee, C.W., Choi, E.J., Yoon, S.K., Ahn, K.S., and Sung, Y.C. (2002). Hepatitis C virus core inhibits the Fasmediated p38 mitogen activated kinase signaling pathway in hepatocytes. Mol. Cells 13, 452–462.
Author information
Authors and Affiliations
Corresponding author
Additional information
These authors contributed equally to this work.
About this article
Cite this article
Feng, G., Zhang, JY., Zeng, QL. et al. HCV-specific interleukin-21+CD4+ T cells responses associated with viral control through the modulation of HCV-specific CD8+ T cells function in chronic hepatitis C patients. Mol Cells 36, 362–367 (2013). https://doi.org/10.1007/s10059-013-0181-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10059-013-0181-z