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Science 324 (5934): 1569-1572

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

IL-21 Is Required to Control Chronic Viral Infection

Heidi Elsaesser,1 Karsten Sauer,2 David G. Brooks1,*

Abstract: CD4+ and CD8+ T cell functions are rapidly aborted during chronic infection, preventing viral clearance. CD4+ T cell help is required throughout chronic infection so as to sustain CD8+ T cell responses; however, the necessary factor(s) provided by CD4+ T cells are currently unknown. Using a mouse model of chronic viral infection, we demonstrated that interleukin-21 (IL-21) is an essential component of CD4+ T cell help. In the absence of IL-21 signaling, despite elevated CD4+ T cell responses, CD8+ T cell responses are severely impaired. CD8+ T cells directly require IL-21 to avoid deletion, maintain immunity, and resolve persistent infection. Thus, IL-21 specifically sustains CD8+ T cell effector activity and provides a mechanism of CD4+ T cell help during chronic viral infection.

1 Department of Microbiology, Immunology, and Molecular Genetics and University of California, Los Angeles (UCLA) AIDS Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
2 Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.

* To whom correspondence should be addressed. E-mail: dbrooks{at}

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J. Virol. 87, 3382-3392
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J. Virol. 87, 1373-1384
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J. Exp. Med. 209, 1391-1395
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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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)
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   Abstract »    Full Text »    PDF »
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J.-H. Cho, H.-O. Kim, K. Webster, M. Palendira, B. Hahm, K.-S. Kim, C. King, S. G. Tangye, and J. Sprent (2011)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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L. M. Fahey, E. B. Wilson, H. Elsaesser, C. D. Fistonich, D. B. McGavern, and D. G. Brooks (2011)
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   Abstract »    Full Text »    PDF »
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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.
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J. Immunol. 186, 5131-5141
   Abstract »    Full Text »    PDF »
HIV and Tuberculosis: a Deadly Human Syndemic.
C. K. Kwan and J. D. Ernst (2011)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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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 »
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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)
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   Abstract »    Full Text »    PDF »
Functional Characterization of a Nonmammalian IL-21: Rainbow Trout Oncorhynchus mykiss IL-21 Upregulates the Expression of the Th Cell Signature Cytokines IFN-{gamma}, IL-10, and IL-22.
T. Wang, P. Diaz-Rosales, M. M. Costa, S. Campbell, M. Snow, B. Collet, S. A. M. Martin, and C. J. Secombes (2011)
J. Immunol. 186, 708-721
   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)
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   Abstract »    Full Text »    PDF »
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I. L. King, K. Mohrs, and M. Mohrs (2010)
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   Abstract »    Full Text »    PDF »
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J. S. Yi, J. T. Ingram, and A. J. Zajac (2010)
J. Immunol. 185, 4835-4845
   Abstract »    Full Text »    PDF »
T Cell Immunity in Acute HIV-1 Infection.
H. Streeck and D. F. Nixon (2010)
The Journal of Infectious Disease 202, S302-S308
   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 »
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 »
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 »
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 »
Dendritic Cell Inhibition Is Connected to Exhaustion of CD8+ T Cell Polyfunctionality during Chronic Hepatitis C Virus Infection.
I. G. Rodrigue-Gervais, H. Rigsby, L. Jouan, D. Sauve, R.-P. Sekaly, B. Willems, and D. Lamarre (2010)
J. Immunol. 184, 3134-3144
   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 »
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 »
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L. D. S. Johnson and S. C. Jameson (2009)
Science 324, 1525-1526
   Abstract »    Full Text »    PDF »

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