Tissue-specific positive feedback requirements for production of type I interferon following virus infection

Type I interferon (IFN) is synthesized by most nucleated cells following viral infection. Robust IFN production in cell culture requires positive feedback expression of inducible signaling components, such as the transcription factor IRF7. However, the role of positive feedback and IRF7 in vivo may be more complex. We found that IFN produced locally in the respiratory tract of influenza virus-infected mice displayed characteristics of positive feedback, including Stat1-dependent induction of IRF7 and IFN gene expression. IRF7 expression was similarly stimulus-dependent in most tissues. However, lymphoid tissue constitutively expressed high levels of IRF7 in the absence of induction or positive feedback, and this expression was largely confined to plasmacytoid dendritic cells (DC). These cells rapidly produced large quantities of multiple IFN alpha species following viral infection without positive feedback, whereas other hematopoietic cells, including other DC subtypes, expressed little IRF7 and were poor IFN producers in the absence of positive feedback. These data reveal a dual mechanism for the regulation of IFN production by differential expression of IRF7, involving positive feedback at local sites of infection combined with robust systemic production by IRF7-expressing plasmacytoid DC.