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: 7391145
• 负责人: CHRISTIAN W SCHINDLER
• 金额: $ 30.42万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391145
• 关键词: Accounting; Antigen-Presenting Cells; Antiviral Agents; Appendix; Area; Binding; Biochemical; Biochemical Genetics; Biological; Cell Nucleus; Cells; Class; Complex; Cytokine Inducible SH2-Containing Protein; Dendritic Cells; Exhibits; Family; Fibroblasts; Gene Expression; Gene Targeting; Genes; Histocompatibility Antigens Class II; Human; IFNAR1 gene; Immune; Immune response; Immunity; In Vitro; Interferon Type I; Interferon Type II; Interferon-alpha; Interferon-beta; Interferons; Investigation; Kinetics; Knockout Mice; MHC Class II Genes; Mediating; Modification; Mus; Nuclear Import; Numbers; Pathogenesis; Pathway interactions; Phosphoric Monoester Hydrolases; Play; Principal Investigator; Property; Proteins; Recruitment Activity; Regulation; Role; Signal Pathway; Signal Transduction; Systemic Lupus Erythematosus; Tissues; Transcriptional Activation; Tyrosine Phosphorylation; Ubiquitin; Up-Regulation; Virus; Virus Diseases; cytokine; macrophage; man; programs; protein inhibitors of activated STAT; receptor; response; transcription factor; type I interferon receptor; ubiquitin-protein ligase

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鉴定，可分为两大类。其中，II 型或免疫 IFN（又名 IFN-γ）已声名狼藉，但 I 型 IFN（IFN-Is；例如 IFN-α、IFN-β 等）代表了一个更大且复杂的家族。与此相一致的是，病毒已经进化出多种策略来阻止 IFN-I 活性。最近，IFN-Is 也引起了一些关注，人们认识到它们是类浆树突状细胞（pDC，又名“天然 IFN-I 产生细胞”）分泌的主要效应细胞因子。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 pDC 在系统性红斑狼疮 (SLE) 的发病机制中发挥着重要作用。 与其他细胞因子一样，IFN-Is 通过诱导新基因来诱导其有效活性。 IFN-α 快速诱导基因能力的表征导致了 Stat1 和 Stat2（前两个 STAT 转录因子）的鉴定。这些 STAT 通过未知机制被招募到 I 型干扰素受体 (IFNAR)，随后它们被激活（通过酪氨酸磷酸化）、二聚化、易位到细胞核并激活基因。相比之下，IFN-gamma 仅通过 Stat1 转导其信号，尽管动力学不同。 为了确定 Stat2 在 IFN-Is 生物反应中发挥的独特作用，我们培育了 Stat2 敲除小鼠。这些小鼠对病毒感染高度敏感，并且对 IFN-Is 部分无反应。出乎意料的是，它们在 IFN-I 刺激的 Stat1 激活方面表现出组织特异性差异，并且在主要组织相容性复合物 II 类 (MHC-II) 的正常调节方面丧失。这些观察结果强调了 I 型干扰素在调节先天性和适应性免疫中发挥的重要作用。为了了解 IFN-Is 如何介导其许多有效作用，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Stat2在调节巨噬细胞MHC-II表达中所表现出的独特作用 3. 探索SUMO化在调节IFN刺激的STATs动力学中可能发挥的作用。