Type 1 IFN Function and Signaling in Immunity to Viruses

先天的细胞因子，1型干扰素，包括干扰素α和β，首先被鉴定为 它们的抗病毒功能。现在已经知道，它们还调节一系列广泛的免疫调节效应。 其中某些是矛盾的，控制干扰素-2诱导的效应子集的机制- 阿尔法/贝塔暴露仍有待阐明。同样，CD8 T细胞的调节也不完全清楚，但 在引起高浓度1型病毒感染期间观察到戏剧性的CD8 T细胞反应 IFN。该项目将检验第一型干扰素效应受以下因素控制的基本假设 对不同细胞内信号通路的调节，并且这种调节是必需的，并且 在对病毒感染的先天和获得性免疫反应期间提供。因此，这些假设提出了 I型干扰素是病毒先天免疫反应和获得性免疫反应之间的纽带 基于我们对信号转导和转录激活子(STAT)功能的研究1 和STAT4在感染淋巴细胞性脉络膜脑膜炎病毒(LCMV)和治疗后 细胞因子，STAT1的调节被认为是切换到不同反应的关键机制 在暴露于1型干扰素之后。计划中的实验重点将放在抗病毒诱导的效果上。 状态，干扰素-α/β扩增，以及CD8T细胞干扰素-γ的产生和增殖反应。 这项工作将按三个具体目标完成。目的1将评估感染诱导的变化。 1型干扰素对靶基因表达的影响。目标2将定义STAT函数在塑造 1型干扰素介导的生物学效应。这一目标将解决统计数据下游的后果。目标3 是否会从机械上促进对如何监管统计数据以促进特定效果的理解。AS 这些研究是由体内生物学的特征驱动的，他们的结果可能会导致发现 体外研究没有预测到的新途径赎罪了。他们将有助于理解 促进抵抗感染的因素，特别是先天免疫成分。他们还承诺 为感染、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和 对投标恐怖主义的防御。

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.