%0 Journal Article %T Functional Crosstalk between Type I and II Interferon through the Regulated Expression of STAT1 %A Daniel J. Gough %A Nicole L. Messina %A Linda Hii %A Jodee A. Gould %A Kanaga Sabapathy %A Ashley P. S. Robertson %A Joseph A. Trapani %A David E. Levy %A Paul J. Hertzog %A Christopher J. P. Clarke %A Ricky W. Johnstone %J PLOS Biology %D 2012 %I Public Library of Science (PLoS) %R 10.1371/journal.pbio.1000361 %X Autocrine priming of cells by small quantities of constitutively produced type I interferon (IFN) is a well-known phenomenon. In the absence of type I IFN priming, cells display attenuated responses to other cytokines, such as anti-viral protection in response to IFN¦Ã. This phenomenon was proposed to be because IFN¦Á/¦Â receptor1 (IFNAR1) is a component of the IFN¦Ã receptor (IFNGR), but our new data are more consistent with a previously proposed model indicating that regulated expression of STAT1 may also play a critical role in the priming process. Initially, we noticed that DNA binding activity of STAT1 was attenuated in c-Jun£¿/£¿ fibroblasts because they expressed lower levels of STAT1 than wild-type cells. However, expression of STAT1 was rescued by culturing c-Jun£¿/£¿ fibroblasts in media conditioned by wild-type fibroblasts suggesting they secreted a STAT1-inducing factor. The STAT1-inducing factor in fibroblast-conditioned media was IFN¦Â, as it was inhibited by antibodies to IFNAR1, or when IFN¦Â expression was knocked down in wild-type cells. IFNAR1£¿/£¿ fibroblasts, which cannot respond to this priming, also expressed reduced levels of STAT1, which correlated with their poor responses to IFN¦Ã. The lack of priming in IFNAR1£¿/£¿ fibroblasts was compensated by over-expression of STAT1, which rescued molecular responses to IFN¦Ã and restored the ability of IFN¦Ã to induce protective anti-viral immunity. This study provides a comprehensive description of the molecular events involved in priming by type I IFN. Adding to the previous working model that proposed an interaction between type I and II IFN receptors, our work and that of others demonstrates that type I IFN primes IFN¦Ã-mediated immune responses by regulating expression of STAT1. This may also explain how type I IFN can additionally prime cells to respond to a range of other cytokines that use STAT1 (e.g., IL-6, M-CSF, IL-10) and suggests a potential mechanism for the changing levels of STAT1 expression observed during viral infection. %U http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000361