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

• Published in: Science (American Association for the Advancement of Science) 2002-09, Vol.297 (5589), p.2063-2066
• Main Authors: Nguyen, Khuong B., Watford, Wendy T., Salomon, Rachelle, Hofmann, Sigrun R., Pien, Gary C., Morinobu, Akio, Gadina, Massimo, O'Shea, John J., Biron, Christine A.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antiviral agents; Arenaviridae Infections - immunology; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cells, Cultured; Cytokines; DNA-Binding Proteins - metabolism; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation; Immunobiology; Immunology; Infections; Interferon; Interferon Type I - immunology; Interferon Type I - pharmacology; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Interferons; Interleukin-12 - physiology; Leukocytes; Lymphocytic choriomeningitis virus; Male; Mice; Mice, Inbred C57BL; Modulation of the immune response (stimulation, suppression); Phosphorylation; Physiological regulation; Promoter Regions, Genetic; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Recombinant Proteins; Signal Transduction; STAT1 Transcription Factor; STAT4 Transcription Factor; Student Financial Aid; T lymphocytes; Th1 Cells - immunology; Th1 Cells - metabolism; Trans-Activators - metabolism; Viral infections; Viruses
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1074900

Interferons (IFNs) are essential for host defense. Although the antiviral effects of the type 1 IFNs IFN-α and IFN-β (IFN-α/β) have been established, their immunoregulatory functions, especially their ability to regulate IFN-γ production, are poorly understood. Here we show that IFN-α/β activate STAT4 directly (STAT, signal transducers and activators of transcription) and that this is required for IFN-γ production during viral infections of mice, in concert with T cell receptor-derived signals. In contrast, STAT1 appears to negatively regulate IFN-α/β induction of IFN-γ. 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.