Abstract
Induction of high systemic levels of type 1 interferons (IFNs) IFN-α and IFN-β is a hallmark of many viral infections. In addition to their potent antiviral effects, these cytokines mediate a number of immunoregulatory functions and can promote IFN-γ expression in T cells. However, during viral infections of mice IFN-γ production is not always observed at the same time as systemic IFN-α/β production and when, elicited at these times, is IFN-α/βâindependent. We demonstrate that type 1 interferons not only fail to induce, but also act to inhibit, IFN-γ expression by both NK and T cells. The mechanism of inhibition is dependent upon the IFN-α/β receptor and the signal transducer and activator of transcription 1 (STAT1). In the absence of STAT1, not only are the IFN-α/βâmediated inhibitory effects completely abrogated, but the cytokines themselves can induce IFN-γ expression. These results indicate that endogenous biochemical pathways are in place to negatively regulate NK and T cell IFN-γ expression elicited by IFN-α/β or other stimuli, at times of innate responses to viral infections. They also show that type 1 interferon signaling can occur through STAT1-dependent and independent mechanisms and suggest that efficient induction of IFN-γ expression by IFN-α/β requires STAT1 regulation. Such immunoregulatory pathways may be critical for shaping the endogenous innate and virus-specific adaptive immune responses to viral infections.
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Acknowledgements
We thank Stacey Carlton, Marc Dalod, Ryuta Nishikomori, Philipp Osterloh, Melanie Ruzek, and Thais Salazar-Mather for their help with experiments and/or stimulating discussions; Eugene Chin for careful reading of the manuscript; and Michael Brunda, Ion Gresser, Phil Scott, Robert Seder, Warren Strober, and Giorgio Trinchieri, for valuable gifts of reagents. This work was supported by grants R01-CA41268 and T32-ES07272 from the National Institutes of Health, and by a pre-doctoral fellowship from HHMI.
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Nguyen, K., Cousens, L., Doughty, L. et al. Interferon α/β-mediated inhibition and promotion of interferon γ: STAT1 resolves a paradox. Nat Immunol 1, 70â76 (2000). https://doi.org/10.1038/76940
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DOI: https://doi.org/10.1038/76940
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