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: 6884818
• 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/6884818
• 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），首先被鉴定为有效的抗病毒活性，可分为两大类。其中，II型或免疫IFN（a.k.a. IFN-γ）已经赢得了很多恶名，但是I型IFN（IFN-1;例如，IFN-α、IFN-β等）代表了一个更大更复杂的家庭与此一致，病毒已经进化出许多策略来阻碍IFN-1活性。最近，IFN-1也获得了一些知名度，认识到它们是由浆细胞样树突细胞（pDC，a.k.a.“天然IFN-I产生细胞”）。这些IFN-I然后调节先天免疫和适应性免疫两者的方面。还有有趣的新证据表明，IFN-1和pDC在系统性红斑狼疮（SLE）的发病机制中起重要作用。 与其他细胞因子一样，IFN-1通过诱导新基因来诱导其有效活性。IFN-α快速诱导基因的能力的表征导致了前两个STAT转录因子Stat 1和Stat 2的鉴定。这些STAT通过未知的机制被募集到I型IFN受体（IFNAR），于是它们被激活（通过酪氨酸磷酸化）、二聚化、易位到细胞核并激活基因。相反，IFN-γ仅通过Stat 1转导其信号，尽管动力学不同。 为了确定Stat 2在对IFN-1的生物学应答中发挥的独特作用，产生了Stat 2敲除小鼠。这些小鼠对病毒感染高度敏感，并且对IFN-1部分无反应。出乎意料的是，它们在IFN-1刺激的Stat 1活化和II类主要组织相容性复合物（MHC-II）的正常调节中表现出组织特异性差异。这些观察结果强调了I型IFN在调节先天性和适应性免疫中的重要作用。为了了解IFN-1是如何介导其许多有效作用的，我们建议： 1.确定STAT如何在I型IFN受体上被激活，包括组织特异性差异。 2.确定Stat 2在调节巨噬细胞MHC-II表达中的独特作用 3.探索SUMO化在调节IFN刺激的STAT的动力学中可能发挥的作用。