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Interferon α/β-mediated inhibition and promotion of interferon γ: STAT1 resolves a paradox

Nature Immunology volume 1, pages 70–76 (2000)Cite this article

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/β–independent. 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/β–mediated 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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Figure 1: Infection-induced leukocyte refractoriness to IL-12 stimulation of IFN-γ.
Figure 2: IL-12Rβ1 and IL-12Rβ2 expression on NK cells in uninfected or virus-infected mice.
Figure 3: IFN-α/β-mediated induction of leukocyte refractoriness to IL-12 stimulation of IFN-γ.
Figure 4: IFN-α/β–mediated induction of leukocyte refractoriness to anti-CD3 stimulation of IFN-γ.
Figure 5: STAT1-mediated leukocyte refractoriness to IL-12 or anti-CD3 stimulation for IFN-γ production in vitro.
Figure 6: IFN-α/βR- and STAT1-mediated regulation of IFN-γ responses during viral infections.
Figure 7: Type 1 IFN stimulation of IFN-γ production in the absence of STAT1.

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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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Authors and Affiliations

  1. Department of Molecular Microbiology and Immunology, Brown University, Providence, 02912, Rhode Island, USA

    Khuong B. Nguyen, Leslie P. Cousens, Lesley A. Doughty, Gary C. Pien & Christine A. Biron

  2. Department of Pediatrics, Division of Biology and Medicine, Brown University, Providence, 02912, Rhode Island, USA

    Lesley A. Doughty

  3. Department of Pathology, The Ohio State University, Columbus, 43210, Ohio, USA

    Joan E. Durbin

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Correspondence to Christine A. Biron.

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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, 70–76 (2000). https://doi.org/10.1038/76940

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