IFN-Is at the interface of Innate and Adapative Immunity

IFN-Is 位于先天免疫和适应性免疫的界面

• 批准号: 6827954
• 负责人: CHRISTIAN W SCHINDLER
• 金额: $ 32.7万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827954
• 关键词: MHC class II antigen; RNase protection assay; biological signal transduction; chromatin immunoprecipitation; cytokine receptors; gene targeting; genetically modified animals; immunity; immunoconjugates; interferons; laboratory mouse; macrophage; protein structure function; transcription factor

DESCRIPTION (provided by applicant): Interferons (IFNs), first identified for their potent antiviral activity, can be divided into two major classes. Of these, type II or immune IFN (a.k.a. IFN-gamma) has earned much notoriety, but the type I IFNs (IFN-Is; e.g., IFN-alpha, IFN-beta, etc.) represent a much larger and complex family. Consistent with this, viruses have evolved numerous strategies to thwart IFN-I activity. More recently, IFN-Is have also achieved some celebrity with the recognition that they are the major effector cytokine secreted by plasmacvtoid dendritic cells (pDCs, a.k.a. "Natural IFN-I Producing Cells"). These IFN-Is then regulate aspects of both innate and adaptive immunity. There is also intriguing new evidence that IFN-Is and pDCs play an important role in the pathogenesis of Systemic Lupus Erythematosis (SLE). Like other cytokines, IFN-Is induce their potent activity through the induction of new genes. Characterization of the ability of IFN-alpha to rapidly induce genes led to the identification of Stat1 and Stat2, the first two STAT transcription factors. These STATs are recruited to the type I IFN receptor (IFNAR) by unknown mechanisms, whereupon they become activated (by tyrosine phosphorylation), dimerize, translocate to the nucleus and activate genes. In contrast, IFN-gamma transduces its signals solely through Stat1, albeit with differing kinetics. To determine the unique role Stat2 plays in the biological response to IFN-Is, Stat2 knockout mice were generated. These mice were highly susceptible to viral infection and partially unresponsive to IFN-Is. Unexpectedly, they exhibited tissue-specific differences in IFN-I stimulated Statl activation and a loss in the normal regulation of the Major Histocompatibility Complex class II (MHC-II). These observations highlight the important role type I IFNs play in regulating innate and adaptive immunity. To understand how IFN-Is mediate their many potent effects we propose to: 1. Determine how STATs are activated at the type I IFN receptor, including tissue specific differences. 2. Determine the unique role Stat2 exhibits in regulating MHC-II expression in macrophages 3. Explore the role SUMOylation may play in regulating the kinetics of IFN stimulated STATs.

描述（由申请人提供）：首先确定其有效抗病毒活动的干扰素（IFNS）可以分为两个主要类别。其中，II型或免疫IFN（又称IFN-GAMMA）赢得了很多声名狼藉，但是I型IFN（IFN-IS;例如IFN-Alpha，IFN-BETA等）代表了一个更大而复杂的家族。与此一致，病毒已经发展了许多策略，以阻止IFN-I活性。最近，IFN-IS也认识到它们是plasmacvtoid Dendritic细胞分泌的主要效应子细胞因子（PDCS，又称“天然IFN-I产生细胞”）。这些IFN-IS然后调节先天和适应性免疫的各个方面。也有有趣的新证据表明，IFN-IS和PDC在全身性红斑狼疮（SLE）的发病机理中起着重要作用。 像其他细胞因子一样，IFN-IS通过诱导新基因诱导其有效活性。 IFN-Alpha快速诱导基因的能力的表征导致STAT1和STAT2（前两个Stat转录因子）的鉴定。这些统计数据通过未知机制募集到I型IFN受体（IFNAR）中，因此它们被激活（通过酪氨酸磷酸化），二聚体，转移到细胞核并激活基因。相比之下，IFN-GAMMA仅通过STAT1传递其信号，尽管动力学不同。 为了确定STAT2在对IFN-IS的生物学反应中的独特作用，产生了STAT2敲除小鼠。这些小鼠非常容易受到病毒感染的影响，并且对IFN-IS有部分反应。出乎意料的是，它们在IFN-I刺激的Statl激活中表现出组织特异性的差异，并且在主要的组织相容性复合物II类（MHC-II）的正常调控中丧失。这些观察结果突出了I型IFN在调节先天和适应性免疫方面发挥的重要作用。要了解IFN-IS如何调解它们的许多有效效果，我们建议： 1。确定如何在I型IFN受体（包括组织特异性差异）处激活统计数据。 2。确定STAT2在调节巨噬细胞中MHC-II表达中表现出的独特作用 3。探索Sumoylation的作用可能在调节IFN刺激统计数据的动力学方面起着作用。