INFLUENZA-A VIRUS-INDUCED IFN-ALPHA BETA AND IL-18 SYNERGISTICALLY ENHANCE IFN-GAMMA GENE-EXPRESSION IN HUMAN T-CELLS/

T cells contribute significantly the to host's early defense against v iral and bacterial infections and are essential for clearance of the p athogen, IFN-gamma, a product of activated T and NK cells, has, in add ition to its direct antimicrobial activity, a major role in activating cell-mediated immunity. Here we report that cytokines secreted by inf luenza A virus-infected macrophages are able to induce IFN-gamma synth esis in human T cells. Influenza A virus-infected human peripheral mac rophages secreted IFN-alpha/beta, TNF-alpha IL-1 beta, and a recently identified cytokine, IL-18 (or IFN-gamma-inducing factor), whereas the production of IL-12 was not detected. Supernatants collected from vir us-infected macrophages induced rapid IFN-gamma mRNA expression and pr otein production in T cells. This was down-regulated by the addition o f neutralizing anti-IFN-alpha/beta Abs, whereas neutralizing anti-IL-1 2 Abs had no effect on IFN-gamma gene expression. Exogenously added IF N-alpha/beta also rapidly stimulated the synthesis of IFN-gamma mRNA i n T cells independently of protein synthesis. IL-18 synergized with IF N-alpha to up-regulate IFN-gamma gene expression and protein productio n. The data suggest that IFN-alpha/beta and IL-18 produced by macropha ges during virus infection may act together to induce IFN-gamma synthe sis and, consequently, may play an important role for both of these cy tokines in the development of Th1-type immune responses.