The type 1 interferons (IFNs), including the IFNs alpha and beta, have potent antiviral effects, but also mediate a wide range of immunoregulatory functions. These include effects on lymphocyte subsets. Some are paradoxical, and the mechanisms controlling type 1 IFN effects, to allow access to subset functions when needed, are poorly characterized. The cytokines do stimulate a signaling pathway, depending on the signal transducers and activators of transcription (STAT) 1 and 2, but they can conditionally activate all of the STATs, including STAT4. As a result of experiments demonstrating that total STAT1 protein is dramatically induced at early times after infection, and that type 1 IFN activation of STAT4 negatively correlates with STAT1 levels, this project proposed to test the hypotheses that type 1 IFN effects 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. The work has proven the hypotheses to be correct, and subset responses linked to different pathways are being defined. Experiments are proposed in this renewal application to test the hypotheses that STATs act as molecular switches in promoting cellular responses by both enhancing and inhibiting type 1 IFN effects, and that the STAT1 and STAT4 effects on the reciprocal signaling pathway are influenced by, and have consequences for, other STAT molecules. This will be accomplished through four specific aims focusing on T cell responses.
Aim 1 will broaden the understanding of STAT expression and the consequences of changes for type 1 IFN access to individual STATs in different T cell subsets during infection.
Aim 2 will mechanistically define the pathways regulating STAT levels.
Aim 3 will test the hypothesis that STATs act as master switches by evaluating the consequences of experimentally modulating STAT levels and the mechanisms for resulting positive and negative effects on cellular responses ex vivo.
Aim 4 will define the importance of modulating STAT switches for regulating biological responses during infections. Immunological, virological, biochemical, and molecular techniques will be used, and the work will be advanced by studies of responses ex vivo following exposure to cytokines, and in vivo following lymphocytic choriomeningitis virus infections in wild type and genetically altered mice. The project promises to continue to advance understanding of the control of type 1 IFN effects in shaping immune responses to infection, and to provide insights for use of cytokines in therapeutic applications. Even more broadly, however, it will identify paradigms for how cytokine effects are regulated to add value to a limited number of genes.

Public Health Relevance

The type 1 interferons (IFNs) mediate a wide range of biological effects, and some of these are paradoxical. This work is directed at understanding how their functions are regulated to access and control subset responses as needed in promoting health during infections. Because type 1 IFNs are also being used, with uneven success, in the treatments of cancer, chronic hepatitis C virus infections, and multiple sclerosis, and ablation protocols are being developed to block their contribution to autoimmune diseases, the results have broad relevance for the design of therapeutic protocols in protection against disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Immunity and Host Defense Study Section (IHD)
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Cassetti, Cristina
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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
Suarez-Ramirez, Jenny E; Tarrio, Margarite L; Kim, Kwangsin et al. (2014) CD8 T cells in innate immune responses: using STAT4-dependent but antigen-independent pathways to gamma interferon during viral infection. MBio 5:e01978-14
Tarrio, Margarite L; Lee, Seung-Hwan; Fragoso, Maria F et al. (2014) Proliferation conditions promote intrinsic changes in NK cells for an IL-10 response. J Immunol 193:354-63
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
Gil, M Pilar; Ploquin, Mickael J Y; Watford, Wendy T et al. (2012) Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function. Blood 120:3718-28
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
Mack, Ethan A; Kallal, Lara E; Demers, Delia A et al. (2011) Type 1 interferon induction of natural killer cell gamma interferon production for defense during lymphocytic choriomeningitis virus infection. MBio 2:

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