Type 1 IFN Function and Signaling in Immunity to Viruses

先天性细胞因子，1型干扰素（IFN），包括干扰素α和β，首先被鉴定， 抗病毒功能。现在知道它们还介导广泛的免疫调节作用。 其中某些是矛盾的，控制IFN-γ诱导的效应子集的机制是相互矛盾的。 α/β暴露仍有待阐明。同样，CD8 T细胞调节也不完全清楚， 在病毒感染期间观察到显著的CD8 T细胞应答， 干扰素。本项目将测试的主要假设，1型干扰素的影响引起的控制， 调节进入不同的细胞内信号通路，这种调节是必需的， 在对病毒感染的先天性和适应性免疫应答期间递送。因此，这些假设 1型干扰素作为对病毒的先天性和适应性免疫反应之间的联系 感染"。基于我们对信号转导和转录激活因子（STAT）1功能的研究， 在淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染和用 细胞因子，STAT1的调节被认为是切换到不同反应的关键机制 1型干扰素暴露后。计划实验的重点将是诱导抗病毒药物的作用。 状态、IFN-α/β扩增以及CD8 T细胞IFN-γ产生和增殖反应。 这项工作将在三个具体目标下完成。目的1将评估感染引起的变化， 1型IFN对靶基因表达的影响。目标2将定义STAT在塑造 1型干扰素介导的生物学效应。这一目标将解决STAT下游的后果。目标3 将在机制上推进对STAT如何被调节以促进特定效果的理解。作为 这些研究是由体内生物学特性驱动的，其结果可能导致发现 体外研究未预测的新途径。他们将有助于了解 这些因素，特别是先天免疫成分，促进对感染的抵抗力。他们还承诺， 为治疗感染、癌症和癌症的治疗干预方法提供见解， 免疫缺陷从这项工作中获得的信息将有助于制定准备计划， 防御生物恐怖主义

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 IFN- alpha/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 wilt 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 mediatd 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 atone. 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 biD-terrorism.