The innate cytokines, type 1 interferons (IFN), including interferons alpha and beta, were first identified by their anitiviral functions. It is now know that they also mediate a wide range of immunoregulatory effects. Certain of these are paradoxical, and mechanisms controlling the subset of effects induced following IFNalpha/ beta exposure remain to be elucidated. Likewise, CD8 T cell regulation is incompletely understood, but dramatic CD8 T cell responses are observed during viral infections eliciting high concentrations of type 1 IFNs. This project will test the primary hypotheses that the type 1 IFN effects elicited are controlled by regulation of access to different intracellular signaling pathways, and that this regulation is required and delivered during innate and adaptive immune responses to viral infections. Thus, these hypotheses present a picture of """"""""Type 1 Interferons as Links Between Innate and Adaptive Immune Responses to Viral Infections"""""""". Based on our studies of functions for signal transducers and activators of transcription (STAT) 1 and STAT4 following infections with lymphocytic choriomeningitis virus (LCMV) and treatments with cytokines, regulation of STAT1 is proposed to be a critical mechanism for switching to different responses following type 1 IFN exposure. Focus of the planned experiments will be on effects for induction of antiviral state, IFN-alpha/beta amplification, and the CD8 T cell IFN-gamma production and proliferative responses. The work will be accomplished in three specific aims.
Aim 1 will evaluate the infection-induced changes in type 1 IFN effects for target gene expression.
Aim 2 will define STAT functions in pathways shaping the biological effects mediated by type 1 IFNs.
This aim will address consequences downstream of STATs.
Aim 3 will mechnistically advance understanding of how the STATs are regulated to promote particular effects. As these studies are driven by characterization of in vivo biology, their results are likely to lead to discovery of novel pathways not predicted by in vitro studies alone. They will contribute to the understanding of the factors, particularly the innate immune components, promoting resistance to infections. They also promise to provide insights for approaches to therapeutic intervention in the treatment of infections, cancers, and immunodeficiencies. The information derived from this work will help in devising plans for readiness and defense against bio-terrorism.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SSS-F (01))
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Greenfield, Teri L
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Brown University
Schools of Medicine
United States
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Biron, Christine A; Tarrio, Margarite L (2015) Immunoregulatory cytokine networks: 60 years of learning from murine cytomegalovirus. Med Microbiol Immunol 204:345-54
Wynne, Claire; Lazzari, Elisa; Smith, Siobhán et al. (2014) TRIM68 negatively regulates IFN-? production by degrading TRK fused gene, a novel driver of IFN-? downstream of anti-viral detection systems. PLoS One 9:e101503
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Kallal, Lara E; Biron, Christine A (2013) Changing partners at the dance: Variations in STAT concentrations for shaping cytokine function and immune responses to viral infections. JAKSTAT 2:e23504
Mace, Emily M; Hsu, Amy P; Monaco-Shawver, Linda et al. (2013) Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset. Blood 121:2669-77
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Lee, Seung-Hwan; Fragoso, Maria F; Biron, Christine A (2012) Cutting edge: a novel mechanism bridging innate and adaptive immunity: IL-12 induction of CD25 to form high-affinity IL-2 receptors on NK cells. J Immunol 189:2712-6
Vidal, Silvia M; Khakoo, Salim I; Biron, Christine A (2011) Natural killer cell responses during viral infections: flexibility and conditioning of innate immunity by experience. Curr Opin Virol 1:497-512
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