Abstract
Interleukin (IL)-21, a cytokine produced by activated CD4+ T cells, has broad pleiotropic actions that affect the functions of a variety of lymphoid cells. The roles of IL-21 in modulating immunity to infections are currently being defined. Notably, IL-21-mediated cellular and humoral immune responses play an important role in determining the outcome of viral infection. This article reviews the current knowledge on the critical role of IL-21 in hepatitis B virus (HBV) infection. As a competent intermediary, IL-21 derived from virus-specific CD4+ T cells plays key roles in sustaining CD8+ T cells and promoting B-cell responses that are essential for effective viral control. However, as a mediator of inflammation, IL-21 is also involved in the development of HBV-induced liver cirrhosis and exacerbating liver injury. Overall, the current data point to IL-21 as an immunomodulatory cytokine in HBV infection. Immunotherapeutic strategies aimed at optimizing the beneficial effects of IL-21 in HBV infection may prove to be a rigorous challenge in the future, as they should foster the strengths of IL-21 while circumventing potential drawbacks.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 2000; 408: 57–63.
Bryant VL, Ma CS, Avery DT, Li Y, Good KL, Corcoran LM et al. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. J Immunol 2007; 179: 8180–8190.
Wei L, Laurence A, Elias KM, O'Shea JJ . IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 2007; 282: 34605–34610.
Coquet JM, Kyparissoudis K, Pellicci DG, Besra G, Berzins SP, Smyth MJ et al. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J Immunol 2007; 178: 2827–2834.
Parrish-Novak J, Foster DC, Holly RD, Clegg CH . Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J Leukoc Biol 2002; 72: 856–863.
Elsaesser H, Sauer K, Brooks DG . IL-21 is required to control chronic viral infection. Science 2009; 324: 1569–1572.
Yi JS, Du M, Zajac AJ . A vital role for interleukin-21 in the control of a chronic viral infection. Science 2009; 324: 1572–1576.
Frohlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT, Weber J et al. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 2009; 324: 1576–1580.
Kared H, Fabre T, Bedard N, Bruneau J, Shoukry NH . Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. PLoS Pathog 2013; 9: e1003422.
Chevalier MF, Julg B, Pyo A, Flanders M, Ranasinghe S, Soghoian DZ et al. HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function. J Virol 2011; 85: 733–741.
Cubas RA, Mudd JC, Savoye AL, Perreau M, van Grevenynghe J, Metcalf T et al. Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nat Med 2013; 19: 494–499.
Kwok SK, Cho ML, Park MK, Oh HJ, Park JS, Her YM et al. Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis. Arthritis Rheum 2012; 64: 740–751.
Fantini MC, Monteleone G, MacDonald TT . IL-21 comes of age as a regulator of effector T cells in the gut. Mucosal Immunol 2008; 1: 110–115.
Maini MK, Boni C, Ogg GS, King AS, Reignat S, Lee CK et al. Direct ex vivo analysis of hepatitis B virus-specific CD8+ T cells associated with the control of infection. Gastroenterology 1999; 117: 1386–1396.
Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH et al. CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 2003; 77: 68–76.
Chisari FV, Isogawa M, Wieland SF . Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris) 2010; 58: 258–266.
Shedlock DJ, Shen H . Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 2003; 300: 337–339.
Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP . CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 2003; 421: 852–856.
Sun JC, Williams MA, Bevan MJ . CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat Immunol 2004; 5: 927–933.
Asabe S, Wieland SF, Chattopadhyay PK, Roederer M, Engle RE, Purcell RH et al. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. J Virol 2009; 83: 9652–9662.
Publicover J, Goodsell A, Nishimura S, Vilarinho S, Wang ZE, Avanesyan L et al. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J Clin Invest 2011; 121: 1154–1162.
Ma SW, Huang X, Li YY, Tang LB, Sun XF, Jiang XT et al. High serum IL-21 levels after 12 weeks of antiviral therapy predict HBeAg seroconversion in chronic hepatitis B. J Hepatol 2012; 56: 775–781.
Li Y, Ma S, Tang L, Li Y, Wang W, Huang X et al. Circulating chemokine (C–X–C Motif) receptor 5+ CD4+ T cells benefit hepatitis B e antigen seroconversion through IL-21 in patients with chronic hepatitis B virus infection. Hepatology 2013; 58: 1277–1286.
Li L, Liu M, Cheng LW, Gao XY, Fu JJ, Kong G et al. HBcAg-specific IL-21-producing CD4+ T cells are associated with relative viral control in patients with chronic hepatitis B. Scand J Immunol 2013; 78: 439–446.
Ren G, Esser S, Jochum C, Schlaak JF, Gerken G, Schadendorf D et al. Interleukin 21 augments the hepatitis B virus-specific CD8+ T-cell response in vitro in patients coinfected with HIV-1. AIDS 2012; 26: 2145–2153.
Crotty S . Follicular helper CD4 T cells (TFH). Annu Rev Immunol 2011; 29: 621–663.
Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A et al. A critical role for IL-21 in regulating immunoglobulin production. Science 2002; 298: 1630–1634.
Klein I, Crispe IN . Complete differentiation of CD8+ T cells activated locally within the transplanted liver. J Exp Med 2006; 203: 437–447.
Wuensch SA, Pierce RH, Crispe IN . Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation. J Immunol 2006; 177: 1689–1697.
Greter M, Hofmann J, Becher B . Neo-lymphoid aggregates in the adult liver can initiate potent cell-mediated immunity. PLoS Biol 2009; 7: e1000109.
Crispe IN . The liver as a lymphoid organ. Annu Rev Immunol 2009; 27: 147–163.
Thomson AW, Knolle PA . Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 2010; 10: 753–766.
Calne RY . Immunological tolerance—the liver effect. Immunol Rev 2000; 174: 280–282.
Knolle PA, Gerken G . Local control of the immune response in the liver. Immunol Rev 2000; 174: 21–34.
Publicover J, Gaggar A, Nishimura S, Van Horn CM, Goodsell A, Muench MO et al. Age-dependent hepatic lymphoid organization directs successful immunity to hepatitis B. J Clin Invest 2013; 123: 3728–3739.
Rasheed MA, Latner DR, Aubert RD, Gourley T, Spolski R, Davis CW et al. Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells. J Virol 2013; 87: 7737–7746.
Lau GK, Wang FS . Uncover the immune biomarkers underlying hepatitis B e antigen (HBeAg) seroconversion: a need for more translational study. J Hepatol 2012; 56: 753–755.
Giarda P, Avihingsanon A, Sasadeusz J, Audsley J, Marks P, Matthews G et al. CXCL-10, interleukin-12 and interleukin-21 are not immunological predictors of HBeAg seroconversion in HIV-1-HBV coinfection following HBV-active antiretroviral therapy. Antivir Ther 2014; 19: 429–433.
Cooksley H, Chokshi S, Maayan Y, Wedemeyer H, Andreone P, Gilson R et al. Hepatitis B virus e antigen loss during adefovir dipivoxil therapy is associated with enhanced virus-specific CD4+ T-cell reactivity. Antimicrob Agents Chemother 2008; 52: 312–320.
Simpson N, Gatenby PA, Wilson A, Malik S, Fulcher DA, Tangye SG et al. Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum 2010; 62: 234–244.
Linterman MA, Vinuesa CG . Signals that influence T follicular helper cell differentiation and function. Semin Immunopathol 2010; 32: 183–196.
Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G et al. Human blood CXCR5+CD4+ T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 2011; 34: 108–121.
Chevalier N, Jarrossay D, Ho E, Avery DT, Ma CS, Yu D et al. CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses. J Immunol 2011; 186: 5556–5568.
Feng J, Lu L, Hua C, Qin L, Zhao P, Wang J et al. High frequency of CD4+ CXCR5+ TFH cells in patients with immune-active chronic hepatitis B. PLoS One 2011; 6: e21698.
Dong C . Regulation and pro-inflammatory function of interleukin-17 family cytokines. Immunol Rev 2008; 226: 80–86.
Zhang JY, Zhang Z, Lin F, Zou ZS, Xu RN, Jin L et al. Interleukin-17-producing CD4+ T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology 2010; 51: 81–91.
Hu X, Ma S, Huang X, Jiang X, Zhu X, Gao H et al. Interleukin-21 is upregulated in hepatitis B-related acute-on-chronic liver failure and associated with severity of liver disease. J Viral Hepat 2011; 18: 458–467.
Pan Q, Yu Y, Tang Z, Xi M, Jiang H, Xun Y et al. Increased levels of IL-21 responses are associated with the severity of liver injury in patients with chronic active hepatitis B. J Viral Hepat 2014; 21: e78–e88.
Sun HQ, Zhang JY, Zhang H, Zou ZS, Wang FS, Jia JH . Increased Th17 cells contribute to disease progression in patients with HBV-associated liver cirrhosis. J Viral Hepat 2012; 19: 396–403.
Pesce J, Kaviratne M, Ramalingam TR, Thompson RW, Urban JJ, Cheever AW et al. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest 2006; 116: 2044–2055.
Feng G, Zhang JY, Zeng QL, Yu X, Zhang Z, Lv S et al. Interleukin-21 mediates hepatitis B virus-associated liver cirrhosis by activating hepatic stellate cells. Hepatol Res 2013; in press.
Acknowledgements
The authors express their sincere thanks to Drs Xiaoyong Zhang and Chris Kafai Li for their critical comments. This work was supported by the Major Science and Technology Special Project of China (2008ZX10002-004, 2012ZX10002-003 and 2011CB946100) and the National Natural Science Foundation of China (81270025).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Li, Y., Tang, L. & Hou, J. Role of interleukin-21 in HBV infection: friend or foe?. Cell Mol Immunol 12, 303–308 (2015). https://doi.org/10.1038/cmi.2014.109
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/cmi.2014.109
Keywords
This article is cited by
-
Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report
BMC Infectious Diseases (2020)
-
Identification of the novel 3′ UTR sequences of human IL-21 mRNA as potential targets of miRNAs
Scientific Reports (2017)
-
Overview of the special issue on HBV immunity
Cellular & Molecular Immunology (2015)