Abstract
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.
Highlights
Type I IFN (IFN␣/)1 is produced by virally infected cells
We found that IFN production correlated with IRF7 production in infected lungs, which was drastically impaired in STAT1-deficient mice, consistent with a requirement for positive feedback
We investigated whether impaired IFN production at the site of infection due to the absence of positive feedback contributed to the phenotype of STAT1-deficient mice
Summary
Type I IFN (IFN␣/) is produced by virally infected cells. These cytokines play important roles in the response to both local and systemic infections by signaling through the type I IFN receptor complex (IFNAR1 and IFNAR2). The importance of feedback and the role of IRF7 were investigated by Kalinke and colleagues [14], who studied IFN␣ production by splenocytes following infection with vesicular stomatitis virus or UV-irradiated Herpes simplex virus They observed that at early time points (Ͻ6 h post-infection), marginal zone splenocytes produced similar quantities of IFN irrespective of whether the mice expressed IFN receptors or not. Tissue-specific IFN-positive Feedback subtype of dendritic cell (DC), known as the plasmacytoid DC (pDC) [16, 17] This cell type appears to have distinct mechanisms for producing IFN [18, 19], at least in response to inducers that signal through Toll-like receptors (TLRs). Systemic infections (e.g. intravenous) may lead to efficient activation of splenic pDC, whereas peripheral infections (e.g. respiratory) may only target localized responsive cell types
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