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Molecular and Cellular Biology, July 2005, p. 5456-5465, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5456-5465.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Stat1 and Stat2 but Not Stat3 Arbitrate Contradictory Growth Signals Elicited by Alpha/Beta Interferon in T Lymphocytes

Ramon Gimeno,1,{dagger} Chien-Kuo Lee,1,{ddagger} Christian Schindler,2 and David E. Levy1*

Departments of Pathology and Microbiology, New York University School of Medicine, New York, New York 10016,1 Department of Microbiology, Columbia University College of Physicians and Surgeons, New York, New York 100322

Received 26 January 2005/ Returned for modification 17 March 2005/ Accepted 11 April 2005

Alpha/beta interferon (IFN-{alpha}/ß) triggers antiviral and antiproliferative responses in target cells through modulation of gene expression. The JAK-STAT pathway is the major mediator of these biological effects through the activation of the transcription factors STAT1 and STAT2, and gene ablation studies have demonstrated that both STAT1 and STAT2 are required for most antiviral responses induced by IFN-{alpha}/ß. However, additional signaling pathways are also activated by IFN. Here, we show that these additional pathways provoke a proliferative response in activated T lymphocytes. While activation of IFN-stimulated gene factor 3 produces a dominant inhibitory signal capable of overriding the mitogenic response, absence of either STAT1 or STAT2 leads to a proliferative response to IFN. Growth stimulation by IFN-{alpha}/ß is independent of other STAT proteins, particularly of STAT3, since T lymphocytes from STAT1-STAT3 double-knockout mice are growth stimulated by IFN-{alpha}/ß treatment. IFN-{alpha}/ß can cooperate with numerous T-cell mitogens, including interleukin-2 (IL-2), IL-4, IL-7, and IL-12, and can contribute to the rapid restoration of the thymus following glucocorticoid-mediated ablation. These results underscore the complexity of the cellular response to IFN and suggest that the ultimate outcome of IFN action results from a balance between growth-inhibitory and -stimulatory effects.

* Corresponding author. Mailing address: Department of Pathology, 550 First Ave. MSB548, New York University School of Medicine, New York, NY 10016. Phone: (212) 263-8192. Fax: (212) 263-8211. E-mail: del243{at}med.nyu.edu.

{dagger} Present address: Department of Cell Biology and Histology, University of Amsterdam, Amsterdam, The Netherlands.

{ddagger} Present address: Institute of Immunology, National Taiwan University College of Medicine, Taipei 100, Taiwan.

Molecular and Cellular Biology, July 2005, p. 5456-5465, Vol. 25, No. 13
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.13.5456-5465.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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