IFN-Is at the interface of Innate and Adpative Immunity

IFN-Is 位于先天免疫和适应性免疫的界面

• 批准号: 7039141
• 负责人: CHRISTIAN W SCHINDLER
• 金额: $ 31.93万
• 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/7039141
• 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）：干扰素（ifn）最初因其有效的抗病毒活性而被发现，可分为两大类。其中，II型或免疫IFN（又名IFN- γ）已经赢得了很多名声，但I型IFN （IFN- is，如IFN- α， IFN- β等）代表了一个更大更复杂的家族。与此一致的是，病毒已经进化出许多策略来阻止IFN-I的活性。最近，IFN-Is也因其是由浆状样树突状细胞（pDCs）分泌的主要效应细胞因子而声名鹊起。“天然IFN-I生成细胞”)。然后这些IFN-Is调节先天免疫和适应性免疫的各个方面。还有有趣的新证据表明，IFN-Is和pDCs在系统性红斑狼疮（SLE）的发病机制中发挥重要作用。