Interferon alpha/beta-mediated inhibition and promotion of interferon gamma: STATI resolves a paradox

Induction of high systemic levels of type I interferons (IFNs) IFN-alpha an d IFN-beta is a hallmark of many viral infections. In addition to their pot ent antiviral effects, these cytokines mediate a number of immunoregulatory functions and can promote IFN-gamma expression in T cells. However, during viral infections of mice IFN-gamma production is not always observed at th e same time as systemic IFN-alpha/beta production and when, elicited at the se times, is IFN-alp-independent. We demonstrate that type I interferons no t only fail to induce, but also act to inhibit, IFN-gamma expression by bot h NK and T cells,The mechanism of inhibition is dependent upon the IFN-alph a/beta receptor and the signal transducer and activator of transcription I (STATI). In the absence of STATI, not only are the IFN-alpha/beta-mediated inhibitory effects completely abrogated, but the cytokines themselves can i nduce IFN-gamma expression. These results indicate that endogenous biochemi cal pathways are in place to negatively regulate NK and T cell IFN-gamma ex pression elicited by IFN-alpha/beta or other stimuli, at times of innate re sponses to viral infections. They also show that type I interferon signalin g can occur through STATI-dependent and independent mechanisms and suggest that efficient induction of IFN-gamma expression by IFN-alpha/beta requires STATI regulation. Such immunoregulatory pathways may be critical for shapi ng the endogenous innate and virus-specific adaptive immune responses to vi ral infections.