Effective immunity to virus infection involves both innate and adaptive host responses. Interferons (IFNs) have long been widely recognized as critical mediators of innate antiviral responses. Type I IFNs, IFNA and IFNB, are the principal antiviral cytokines produced by mammalian cells and function directly on target cells by blocking virus replication. Recently, it has become apparent that type I IFNs may also play a role in adaptive immune responses including T lymphocyte maturation and differentiation, survival, and immunological memory. The regulation of interferon-inducible transcriptional responses which lead to both innate and adaptive antiviral immunity will be investigated. To better understand the role of Type I IFN in regulating both innate and adaptive antiviral responses, the fundamental molecular mechanisms underlying activation of gene expression by the ISGF3 (interferon stimulated gene factor 3) complex will be studied. The transcriptional activity of the ISGF3 subunits will be dissected biochemically using a newly developed hybrid transcription factor approach. Cellular proteins involved in mediating transcription by ISGF3 will be identified and characterized in transcriptional assays. The hybrid IFN transcription factors will be tested for the ability to establish innate antiviral states in cultured cells and tested for their ability to influence T cell signaling and survival in culture. Results of these experiments will be verified in the context of intact IFN signaling. The effects of Type I IFN and the responses initiated by the hybrid IFN transcription factors will be investigated directly in T lymphocytes. The studies in this proposal will provide a biochemical basis for ISGF3 transcriptional activity, test the relationship between innate antiviral effects of ISGF3-induced transcription and adaptive responses to IFN signals, and validate the emerging role of IFN in mediating T cell responses. Successful completion of these studies will greatly enhance our knowledge of cytokine effects on antiviral immune responses.
