Interferon-gamma plays a critical role in host defenses against infection by pathogenic organisms, is produced by cells of the innate and acquired immune system, and is induced by signaling through T cell receptors or through cytokine receptors (IL12R, IL18R). IFNgamma overexpression is a leading factor in progression of autoimmune diseases, including type 1 diabetes, multiple sclerosis, lupus, and rheumatoid arthritis. IFNgamma gene expression is primarily regulated at the level of transcription. How the IFNgamma promoter can be activated by diverse stimuli, such as T cell receptor signaling or cytokine signaling, which activate distinct biochemical pathways, and how the IFNgamma gene can be highly expressed in one T cell subset but silent in other T cell subsets, in response to identical antigen stimulation, are poorly understood biological phenomena. These questions are not simply of academic interest. Answers to these questions should make it possible to """"""""re-polarize"""""""" immune responses to, for example, dampen IFNgamma gene expression to treat autoimmune disease or induce IFNgamma gene expression for more efficient vaccine development. We have developed transgenic mice which express reporter genes under the control of distinct regulatory regions from the IFNgamma gene as tools to uncover transcriptional mechanisms of IFNgamma gene regulation. We hypothesize that three functionally distinct promoters exist within the IFNgamma gene to regulate its transcription. The proximal promoter (P1) is responsive to TCR signaling, a promoter upstream of the proximal promoter (P2) is responsive to cytokine signaling, and a third promoter (P3, within the first intron) inhibits TCR responsiveness of P1 following Th2 differentiation. To test this hypothesis, we will prepare and analyze transgenic mice which express reporter genes (GFP, luciferase) under the control of the IFNgamma gene to uncover the basis for cellular specificity of selective IFNgamma gene expression in subsets of the innate and acquired immune system in response to activation by distinct signaling pathways.
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