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Science 297 (5589): 2063-2066

Copyright © 2002 by the American Association for the Advancement of Science

Critical Role for STAT4 Activation by Type 1 Interferons in the Interferon-gamma Response to Viral Infection

Khuong B. Nguyen,1* Wendy T. Watford,2* Rachelle Salomon,1 Sigrun R. Hofmann,2 Gary C. Pien,1 Akio Morinobu,2 Massimo Gadina,2 John J. O'Shea,2dagger Christine A. Biron1dagger ddagger

Interferons (IFNs) are essential for host defense. Although the antiviral effects of the type 1 IFNs IFN-alpha and IFN-beta (IFN-alpha /beta ) have been established, their immunoregulatory functions, especially their ability to regulate IFN-gamma production, are poorly understood. Here we show that IFN-alpha /beta activate STAT4 directly (STAT, signal transducers and activators of transcription) and that this is required for IFN-gamma production during viral infections of mice, in concert with T cell receptor-derived signals. In contrast, STAT1 appears to negatively regulate IFN-alpha /beta induction of IFN-gamma . Thus, type 1 IFNs, in addition to interleukin-12, provide pathways for innate regulation of adaptive immunity, and their immunoregulatory functions are controlled by modulating the activity of individual STATs.

1 Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA.
2 Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
*   These authors contributed equally to this work.

dagger    These authors contributed equally to this work.

ddagger    To whom correspondence should be addressed. E-mail: christine_biron{at}brown.edu

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B. M. Sullivan, A. Juedes, S. J. Szabo, M. von Herrath, and L. H. Glimcher (2003)
PNAS 100, 15818-15823
   Abstract »    Full Text »    PDF »
Reprogramming of IL-10 Activity and Signaling by IFN-{gamma}.
C. Herrero, X. Hu, W. P. Li, S. Samuels, M. N. Sharif, S. Kotenko, and L. B. Ivashkiv (2003)
J. Immunol. 171, 5034-5041
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Selective Depletion of Nonspecific T Cells During the Early Stage of Immune Responses to Infection.
J. Jiang, L. L. Lau, and H. Shen (2003)
J. Immunol. 171, 4352-4358
   Abstract »    Full Text »    PDF »
Interferon (IFN)-{alpha}/{beta}, interleukin (IL)-12 and IL-18 coordinately induce production of IFN-{gamma} during infection with herpes simplex virus type 2.
L. Malmgaard and S. R. Paludan (2003)
J. Gen. Virol. 84, 2497-2500
   Abstract »    Full Text »    PDF »
Expression and function of chemokines during viral infections: from molecular mechanisms to in vivo function.
J. Melchjorsen, L. N. Sorensen, and S. R. Paludan (2003)
J. Leukoc. Biol. 74, 331-343
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Dendritic Cells Mediate NK Cell Help for Th1 and CTL Responses: Two-Signal Requirement for the Induction of NK Cell Helper Function.
R. B. Mailliard, Y.-I. Son, R. Redlinger, P. T. Coates, A. Giermasz, P. A. Morel, W. J. Storkus, and P. Kalinski (2003)
J. Immunol. 171, 2366-2373
   Abstract »    Full Text »    PDF »
IL-4 synergistically enhances both IL-2- and IL-12-induced IFN-{gamma} expression in murine NK cells.
J. H. Bream, R. E. Curiel, C.-R. Yu, C. E. Egwuagu, M. J. Grusby, T. M. Aune, and H. A. Young (2003)
Blood 102, 207-214
   Abstract »    Full Text »    PDF »
PIASx Is a Transcriptional Co-repressor of Signal Transducer and Activator of Transcription 4.
T. Arora, B. Liu, H. He, J. Kim, T. L. Murphy, K. M. Murphy, R. L. Modlin, and K. Shuai (2003)
J. Biol. Chem. 278, 21327-21330
   Abstract »    Full Text »    PDF »
IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-{gamma} Production in Human NK and T Cells.
M. Strengell, S. Matikainen, J. Siren, A. Lehtonen, D. Foster, I. Julkunen, and T. Sareneva (2003)
J. Immunol. 170, 5464-5469
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Infection-Triggered Regulatory Mechanisms Override the Role of STAT 4 in Control of the Immune Response to Influenza Virus Antigens.
A. Bot, E. Rodrigo, T. Wolfe, S. Bot, and M. G. Von Herrath (2003)
J. Virol. 77, 5794-5800
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Interferon-producing Cells Fail to Induce Proliferation of Naive T Cells but Can Promote Expansion and T Helper 1 Differentiation of Antigen-experienced Unpolarized T Cells.
A. Krug, R. Veeraswamy, A. Pekosz, O. Kanagawa, E. R. Unanue, M. Colonna, and M. Cella (2003)
J. Exp. Med. 197, 899-906
   Abstract »    Full Text »    PDF »
Dendritic Cell Responses to Early Murine Cytomegalovirus Infection: Subset Functional Specialization and Differential Regulation by Interferon {alpha}/{beta}.
M. Dalod, T. Hamilton, R. Salomon, T. P. Salazar-Mather, S. C. Henry, J. D. Hamilton, and C. A. Biron (2003)
J. Exp. Med. 197, 885-898
   Abstract »    Full Text »    PDF »

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