Type 1 IFN Function and Signaling in Immunity to Viruses

描述（由申请人提供）：先天性细胞因子，1型干扰素（IFN），包括干扰素α和β，首先通过其抗病毒功能鉴定。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，和机制控制的影响诱导后IFN α/β暴露的子集仍有待阐明。同样地，CD 8 T细胞调节不完全理解，但在病毒感染引起高浓度的1型IFN期间观察到显著的CD 8 T细胞应答。该项目将测试的主要假设，1型干扰素的影响引起的控制通过调节进入不同的细胞内信号传导途径，这种调节是必需的，并提供在先天性和适应性免疫应答病毒感染。因此，这些假说提出了“1型干扰素作为对病毒感染的先天性和适应性免疫应答之间的联系”的观点。基于我们对淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染和细胞因子治疗后信号转导子和转录激活子（STAT）1和STAT 4功能的研究，提出STAT 1的调节是1型IFN暴露后切换到不同反应的关键机制。计划实验的重点将是对诱导抗病毒状态、IFN-α/β扩增以及CD 8 T细胞IFN-γ产生和增殖反应的影响。这项工作将在三个具体目标下完成。目的1评价感染诱导的1型IFN对靶基因表达的影响。目的2将定义STAT在1型IFN介导的生物学效应形成途径中的功能。这一目标将解决STAT下游的后果。目标3将在机制上促进对STAT如何被调节以促进特定效果的理解。由于这些研究是由体内生物学表征驱动的，因此其结果可能导致发现单独体外研究无法预测的新途径。它们将有助于理解促进对感染的抵抗力的因素，特别是先天免疫成分。它们还有望为感染、癌症和免疫缺陷的治疗干预方法提供见解。从这项工作中获得的信息将有助于制定防备和防御生物恐怖主义的计划。

DESCRIPTION (provided by applicant): 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.