Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 324 (5934): 1572-1576

Copyright © 2009 by the American Association for the Advancement of Science

A Vital Role for Interleukin-21 in the Control of a Chronic Viral Infection

John S. Yi, Ming Du, Allan J. Zajac*

Abstract: Understanding the factors that regulate the induction, quality, and longevity of antiviral T cell responses is essential for devising rational strategies to prevent or combat infections. In this study, we show that interleukin-21 (IL-21), likely produced by CD4+ T cells, directly influences the generation of polyfunctional CD8+ T cells and that the number of CD4+ T cells that produce IL-21 differs markedly between acute and chronic infections. IL-21 regulates the development of CD8+ T cell exhaustion and the ability to contain chronic lymphocytic choriomeningitis virus infection. Thus, IL-21 serves as a critical helper factor that shapes the functional quality of antiviral CD8+ T cells and is required for viral control.

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294–2170, USA.

* To whom correspondence should be addressed. E-mail: azajac{at}uab.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Interleukin-21 Is a Critical Cytokine for the Generation of Virus-Specific Long-Lived Plasma Cells.
M. A. U. Rasheed, D. R. Latner, R. D. Aubert, T. Gourley, R. Spolski, C. W. Davis, W. A. Langley, S.-J. Ha, L. Ye, S. Sarkar, et al. (2013)
J. Virol. 87, 7737-7746
   Abstract »    Full Text »    PDF »
Interleukin-21 Overexpression Dominates T Cell Response to Epstein-Barr Virus in a Fatal Case of X-Linked Lymphoproliferative Syndrome Type 1.
C. Ortega, O. A. Estevez, S. Fernandez, R. Aguado, J. M. Rumbao, T. Gonzalez, J. L. Perez-Navero, and M. Santamaria (2013)
Clin. Vaccine Immunol. 20, 765-771
   Abstract »    Full Text »    PDF »
IL-21 Promotes CD8+ CTL Activity via the Transcription Factor T-bet.
A. P. R. Sutherland, N. Joller, M. Michaud, S. M. Liu, V. K. Kuchroo, and M. J. Grusby (2013)
J. Immunol. 190, 3977-3984
   Abstract »    Full Text »    PDF »
Cutting Edge: STAT1 Is Required for IL-6-Mediated Bcl6 Induction for Early Follicular Helper Cell Differentiation.
Y. S. Choi, D. Eto, J. A. Yang, C. Lao, and S. Crotty (2013)
J. Immunol. 190, 3049-3053
   Abstract »    Full Text »    PDF »
Disparate Roles for STAT5 in Primary and Secondary CTL Responses.
D. M. Mitchell and M. A. Williams (2013)
J. Immunol. 190, 3390-3398
   Abstract »    Full Text »    PDF »
Differential Targeting of Viral Components by CD4+ versus CD8+ T Lymphocytes in Dengue Virus Infection.
L. Rivino, E. A. P. Kumaran, V. Jovanovic, K. Nadua, E. W. Teo, S. W. Pang, G. H. Teo, V. C. H. Gan, D. C. Lye, Y. S. Leo, et al. (2013)
J. Virol. 87, 2693-2706
   Abstract »    Full Text »    PDF »
Alternative Serotype Adenovirus Vaccine Vectors Elicit Memory T Cells with Enhanced Anamnestic Capacity Compared to Ad5 Vectors.
P. Penaloza-MacMaster, N. M. Provine, J. Ra, E. N. Borducchi, A. McNally, N. L. Simmons, M. J. Iampietro, and D. H. Barouch (2013)
J. Virol. 87, 1373-1384
   Abstract »    Full Text »    PDF »
Paucity of IL-21-producing CD4+ T cells is associated with Th17 cell depletion in SIV infection of rhesus macaques.
L. Micci, B. Cervasi, Z. S. Ende, R. I. Iriele, E. Reyes-Aviles, C. Vinton, J. Else, G. Silvestri, A. A. Ansari, F. Villinger, et al. (2012)
Blood 120, 3925-3935
   Abstract »    Full Text »    PDF »
HIV Controllers Maintain a Population of Highly Efficient Th1 Effector Cells in Contrast to Patients Treated in the Long Term.
B. Vingert, D. Benati, O. Lambotte, P. de Truchis, L. Slama, P. Jeannin, M. Galperin, S. Perez-Patrigeon, F. Boufassa, W. W. Kwok, et al. (2012)
J. Virol. 86, 10661-10674
   Abstract »    Full Text »    PDF »
Revealing the role of CD4+ T cells in viral immunity.
A. J. Sant and A. McMichael (2012)
J. Exp. Med. 209, 1391-1395
   Abstract »    Full Text »    PDF »
Regulation of innate CD8+ T-cell activation mediated by cytokines.
B. E. Freeman, E. Hammarlund, H.-P. Raue, and M. K. Slifka (2012)
PNAS 109, 9971-9976
   Abstract »    Full Text »    PDF »
Differential Roles for RIG-I-like Receptors and Nucleic Acid-Sensing TLR Pathways in Controlling a Chronic Viral Infection.
J. M. Clingan, K. Ostrow, K. A. Hosiawa, Z. J. Chen, and M. Matloubian (2012)
J. Immunol. 188, 4432-4440
   Abstract »    Full Text »    PDF »
MHC Class Ib-Restricted CD8 T Cells Differ in Dependence on CD4 T Cell Help and CD28 Costimulation over the Course of Mouse Polyomavirus Infection.
A. R. Hofstetter, M. L. Ford, L. C. Sullivan, J. J. Wilson, A. Hadley, A. G. Brooks, and A. E. Lukacher (2012)
J. Immunol. 188, 3071-3079
   Abstract »    Full Text »    PDF »
Genome-wide scans provide evidence for positive selection of genes implicated in Lassa fever.
K. G. Andersen, I. Shylakhter, S. Tabrizi, S. R. Grossman, C. T. Happi, and P. C. Sabeti (2012)
Phil Trans R Soc B 367, 868-877
   Abstract »    Full Text »    PDF »
Crystal Structure of Interleukin-21 Receptor (IL-21R) Bound to IL-21 Reveals That Sugar Chain Interacting with WSXWS Motif Is Integral Part of IL-21R.
O. J. Hamming, L. Kang, A. Svensson, J. L. Karlsen, H. Rahbek-Nielsen, S. R. Paludan, S. A. Hjorth, K. Bondensgaard, and R. Hartmann (2012)
J. Biol. Chem. 287, 9454-9460
   Abstract »    Full Text »    PDF »
CD4 T Cells Promote CD8 T Cell Immunity at the Priming and Effector Site during Viral Encephalitis.
T. W. Phares, S. A. Stohlman, M. Hwang, B. Min, D. R. Hinton, and C. C. Bergmann (2012)
J. Virol. 86, 2416-2427
   Abstract »    Full Text »    PDF »
IL-21 Can Supplement Suboptimal Lck-Independent MAPK Activation in a STAT-3-Dependent Manner in Human CD8+ T Cells.
O. Imataki, S. Ansen, M. Tanaka, M. O. Butler, A. Berezovskaya, M. I. Milstein, K. Kuzushima, L. M. Nadler, and N. Hirano (2012)
J. Immunol. 188, 1609-1619
   Abstract »    Full Text »    PDF »
IL-21 Promotes the Pathologic Immune Response to Pneumovirus Infection.
R. Spolski, L. Wang, C.-K. Wan, C. A. Bonville, J. B. Domachowske, H.-P. Kim, Z. Yu, and W. J. Leonard (2012)
J. Immunol. 188, 1924-1932
   Abstract »    Full Text »    PDF »
IL-21 Receptor Is Required for the Systemic Accumulation of Activated B and T Lymphocytes in MRL/MpJ-Faslpr/lpr/J Mice.
A. L. Rankin, H. Guay, D. Herber, S. A. Bertino, T. A. Duzanski, Y. Carrier, S. Keegan, M. Senices, N. Stedman, M. Ryan, et al. (2012)
J. Immunol. 188, 1656-1667
   Abstract »    Full Text »    PDF »
Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection.
R. D. Aubert, A. O. Kamphorst, S. Sarkar, V. Vezys, S.-J. Ha, D. L. Barber, L. Ye, A. H. Sharpe, G. J. Freeman, and R. Ahmed (2011)
PNAS 108, 21182-21187
   Abstract »    Full Text »    PDF »
Human CD8+ and CD4+ T Cell Memory to Lymphocytic Choriomeningitis Virus Infection.
M. F. Kotturi, J. A. Swann, B. Peters, C. L. Arlehamn, J. Sidney, R. V. Kolla, E. A. James, R. S. Akondy, R. Ahmed, W. W. Kwok, et al. (2011)
J. Virol. 85, 11770-11780
   Abstract »    Full Text »    PDF »
Late Interleukin-6 Escalates T Follicular Helper Cell Responses and Controls a Chronic Viral Infection.
J. A. Harker, G. M. Lewis, L. Mack, and E. I. Zuniga (2011)
Science 334, 825-829
   Abstract »    Full Text »    PDF »
Cutting Edge: CD40-CD40 Ligand Pathway Plays a Critical CD8-Intrinsic and -Extrinsic Role during Rescue of Exhausted CD8 T Cells.
R. Bhadra, J. P. Gigley, and I. A. Khan (2011)
J. Immunol. 187, 4421-4425
   Abstract »    Full Text »    PDF »
Development of Autoimmune Diabetes in the Absence of Detectable IL-17A in a CD8-Driven Virally Induced Model.
T. L. Van Belle, E. Esplugues, J. Liao, T. Juntti, R. A. Flavell, and M. G. von Herrath (2011)
J. Immunol. 187, 2915-2922
   Abstract »    Full Text »    PDF »
Responsiveness of HIV-specific CD4 T cells to PD-1 blockade.
F. Porichis, D. S. Kwon, J. Zupkosky, D. P. Tighe, A. McMullen, M. A. Brockman, D. F. Pavlik, M. Rodriguez-Garcia, F. Pereyra, G. J. Freeman, et al. (2011)
Blood 118, 965-974
   Abstract »    Full Text »    PDF »
Immunodeficiency lentiviral infections in natural and non-natural hosts.
J. M. Brenchley and M. Paiardini (2011)
Blood 118, 847-854
   Abstract »    Full Text »    PDF »
Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL.
A. M. Hanash, L. W. Kappel, N. L. Yim, R. A. Nejat, G. L. Goldberg, O. M. Smith, U. K. Rao, L. Dykstra, I.-K. Na, A. M. Holland, et al. (2011)
Blood 118, 446-455
   Abstract »    Full Text »    PDF »
Immunotherapeutic effects of IL-7 during a chronic viral infection in mice.
S. G. Nanjappa, E. H. Kim, and M. Suresh (2011)
Blood 117, 5123-5132
   Abstract »    Full Text »    PDF »
Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells.
L. M. Fahey, E. B. Wilson, H. Elsaesser, C. D. Fistonich, D. B. McGavern, and D. G. Brooks (2011)
J. Exp. Med. 208, 987-999
   Abstract »    Full Text »    PDF »
The Role of LAT in Increased CD8+ T Cell Exhaustion in Trigeminal Ganglia of Mice Latently Infected with Herpes Simplex Virus 1.
S. J. Allen, P. Hamrah, D. Gate, K. R. Mott, D. Mantopoulos, L. Zheng, T. Town, C. Jones, U. H. von Andrian, G. J. Freeman, et al. (2011)
J. Virol. 85, 4184-4197
   Abstract »    Full Text »    PDF »
Exposure to IL-15 and IL-21 Enables Autoreactive CD8 T Cells To Respond to Weak Antigens and Cause Disease in a Mouse Model of Autoimmune Diabetes.
S. Ramanathan, S. Dubois, X.-L. Chen, C. Leblanc, P. S. Ohashi, and S. Ilangumaran (2011)
J. Immunol. 186, 5131-5141
   Abstract »    Full Text »    PDF »
HIV and Tuberculosis: a Deadly Human Syndemic.
C. K. Kwan and J. D. Ernst (2011)
Clin. Microbiol. Rev. 24, 351-376
   Abstract »    Full Text »    PDF »
Interleukin-21 Is Critically Required in Autoimmune and Allogeneic Responses to Islet Tissue in Murine Models.
H. M. McGuire, S. Walters, A. Vogelzang, C. M. Y. Lee, K. E. Webster, J. Sprent, D. Christ, S. Grey, and C. King (2011)
Diabetes 60, 867-875
   Abstract »    Full Text »    PDF »
Interleukin-21-Producing HIV-1-Specific CD8 T Cells Are Preferentially Seen in Elite Controllers.
L. D. Williams, A. Bansal, S. Sabbaj, S. L. Heath, W. Song, J. Tang, A. J. Zajac, and P. A. Goepfert (2011)
J. Virol. 85, 2316-2324
   Abstract »    Full Text »    PDF »
Intrinsic IL-21 Signaling Is Critical for CD8 T Cell Survival and Memory Formation in Response to Vaccinia Viral Infection.
P. Novy, X. Huang, W. J. Leonard, and Y. Yang (2011)
J. Immunol. 186, 2729-2738
   Abstract »    Full Text »    PDF »
HIV-1-Specific Interleukin-21+ CD4+ T Cell Responses Contribute to Durable Viral Control through the Modulation of HIV-Specific CD8+ T Cell Function.
M. F. Chevalier, B. Julg, A. Pyo, M. Flanders, S. Ranasinghe, D. Z. Soghoian, D. S. Kwon, J. Rychert, J. Lian, M. I. Muller, et al. (2011)
J. Virol. 85, 733-741
   Abstract »    Full Text »    PDF »
IL-21 induces death of marginal zone B cells during chronic inflammation.
L. Tortola, K. Yadava, M. F. Bachmann, C. Muller, J. Kisielow, and M. Kopf (2010)
Blood 116, 5200-5207
   Abstract »    Full Text »    PDF »
A Nonredundant Role for IL-21 Receptor Signaling in Plasma Cell Differentiation and Protective Type 2 Immunity against Gastrointestinal Helminth Infection.
I. L. King, K. Mohrs, and M. Mohrs (2010)
J. Immunol. 185, 6138-6145
   Abstract »    Full Text »    PDF »
IL-21 Deficiency Influences CD8 T Cell Quality and Recall Responses following an Acute Viral Infection.
J. S. Yi, J. T. Ingram, and A. J. Zajac (2010)
J. Immunol. 185, 4835-4845
   Abstract »    Full Text »    PDF »
Wnt/{beta}-Catenin Signaling in T-Cell Immunity and Cancer Immunotherapy.
L. Gattinoni, Y. Ji, and N. P. Restifo (2010)
Clin. Cancer Res. 16, 4695-4701
   Abstract »    Full Text »    PDF »
Pronounced Virus-Dependent Activation Drives Exhaustion but Sustains IFN-{gamma} Transcript Levels.
K. J. Mackerness, M. A. Cox, L. M. Lilly, C. T. Weaver, L. E. Harrington, and A. J. Zajac (2010)
J. Immunol. 185, 3643-3651
   Abstract »    Full Text »    PDF »
Comparison of OX40 Ligand and CD70 in the Promotion of CD4+ T Cell Responses.
J. S. Kurche, M. A. Burchill, P. J. Sanchez, C. Haluszczak, and R. M. Kedl (2010)
J. Immunol. 185, 2106-2115
   Abstract »    Full Text »    PDF »
Heterogeneity among Viral Antigen-Specific CD4+ T Cells and Their De Novo Recruitment during Persistent Polyomavirus Infection.
E. Lin, C. C. Kemball, A. Hadley, J. J. Wilson, A. R. Hofstetter, C. D. Pack, and A. E. Lukacher (2010)
J. Immunol. 185, 1692-1700
   Abstract »    Full Text »    PDF »
HIV-Specific IL-21 Producing CD4+ T Cells Are Induced in Acute and Chronic Progressive HIV Infection and Are Associated with Relative Viral Control.
F. Y. Yue, C. Lo, A. Sakhdari, E. Y. Lee, C. M. Kovacs, E. Benko, J. Liu, H. Song, R. B. Jones, P. Sheth, et al. (2010)
J. Immunol. 185, 498-506
   Abstract »    Full Text »    PDF »
Germinal Center T Follicular Helper Cell IL-4 Production Is Dependent on Signaling Lymphocytic Activation Molecule Receptor (CD150).
I. Yusuf, R. Kageyama, L. Monticelli, R. J. Johnston, D. DiToro, K. Hansen, B. Barnett, and S. Crotty (2010)
J. Immunol. 185, 190-202
   Abstract »    Full Text »    PDF »
In Vivo Regulation of Bcl6 and T Follicular Helper Cell Development.
A. C. Poholek, K. Hansen, S. G. Hernandez, D. Eto, A. Chandele, J. S. Weinstein, X. Dong, J. M. Odegard, S. M. Kaech, A. L. Dent, et al. (2010)
J. Immunol. 185, 313-326
   Abstract »    Full Text »    PDF »
Distinct Roles for IL-2 and IL-15 in the Differentiation and Survival of CD8+ Effector and Memory T Cells.
D. M. Mitchell, E. V. Ravkov, and M. A. Williams (2010)
J. Immunol. 184, 6719-6730
   Abstract »    Full Text »    PDF »
{gamma}c deficiency precludes CD8+ T cell memory despite formation of potent T cell effectors.
H. Decaluwe, M. Taillardet, E. Corcuff, I. Munitic, H. K. W. Law, B. Rocha, Y. Riviere, and J. P. Di Santo (2010)
PNAS 107, 9311-9316
   Abstract »    Full Text »    PDF »
IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication.
A. Iannello, M. R. Boulassel, S. Samarani, C. Tremblay, E. Toma, J. P. Routy, and A. Ahmad (2010)
J. Leukoc. Biol. 87, 857-867
   Abstract »    Full Text »    PDF »
Cutting Edge: IL-21 and TLR Signaling Regulate Germinal Center Responses in a B Cell-Intrinsic Manner.
J. Bessa, M. Kopf, and M. F. Bachmann (2010)
J. Immunol. 184, 4615-4619
   Abstract »    Full Text »    PDF »
IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection.
D. G. Brooks, K. B. Walsh, H. Elsaesser, and M. B. A. Oldstone (2010)
PNAS 107, 3018-3023
   Abstract »    Full Text »    PDF »
IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism.
D. Zotos, J. M. Coquet, Y. Zhang, A. Light, K. D'Costa, A. Kallies, L. M. Corcoran, D. I. Godfrey, K.-M. Toellner, M. J. Smyth, et al. (2010)
J. Exp. Med. 207, 365-378
   Abstract »    Full Text »    PDF »
A Little 'Help' from IL-21 During Persistent Viral Infection.
D. B. McGavern (2010)
J Mol Cell Biol 2, 8-10
   Abstract »    Full Text »    PDF »
Editorial: Memory CD8 T cells now join "Club 21".
Y. Tagaya (2010)
J. Leukoc. Biol. 87, 13-15
   Abstract »    Full Text »    PDF »
Dynamics and Consequences of IL-21 Production in HIV-Infected Individuals: A Longitudinal and Cross-Sectional Study.
A. Iannello, M.-R. Boulassel, S. Samarani, O. Debbeche, C. Tremblay, E. Toma, J.-P. Routy, and A. Ahmad (2010)
J. Immunol. 184, 114-126
   Abstract »    Full Text »    PDF »
Endogenous IL-21 Restricts CD8+ T Cell Expansion and Is not Required for Tumor Immunity.
H. Sondergaard, J. M. Coquet, A. P. Uldrich, N. McLaughlin, D. I. Godfrey, P. V. Sivakumar, K. Skak, and M. J. Smyth (2009)
J. Immunol. 183, 7326-7336
   Abstract »    Full Text »    PDF »
A Chronic Need for IL-21.
L. D. S. Johnson and S. C. Jameson (2009)
Science 324, 1525-1526
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882