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

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Abstract
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.