The IRF - type I interferon system in T cell-mediated immune tolerance

IRF-I型干扰素系统在T细胞介导的免疫耐受中的作用

• 批准号: 8492601
• 负责人: MICHAEL DAVID
• 金额: $ 18.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492601
• 关键词: Age; American; Antigens; Architecture; Area; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; CD4 Positive T Lymphocytes; CTLA4 gene; Cell Count; Cell Maturation; Cell physiology; Cells; Communicable Diseases; Data; Defect; Development; Developmental Process; Exhibits; Failure; Family member; Feedback; Gene Activation; Generations; Growth Factor; IRF3 gene; Immune Tolerance; Immune response; Immune system; Impairment; Infection; Infectious Agent; Interferon Type I; Interferons; Investigation; Lead; Light; Maintenance; Mediating; Mediator of activation protein; Multiple Sclerosis; Mus; Natural Increases; Peripheral; Play; Population; Predisposition; Prevention; Process; Production; Regulatory T-Lymphocyte; Reporting; Resistance; Role; STAT protein; STAT1 gene; Self Tolerance; Shapes; Signal Transduction; Source; Symptoms; System; T-Cell Activation; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Transcriptional Activation; Woman; adaptive immunity; autocrine; autoreactive T cell; base; cytokine; insight; microbial; novel; pathogen; peripheral tolerance; public health relevance; research study; response; transcription factor

DESCRIPTION (provided by applicant): The innate immune response is an ancient defense system made up of functionally distinct subsystems that have evolved to counter infection by microbial pathogens. The innate response is generally not antigen-specific, and is composed of the interferon (IFN) system, as well as cell-based anti-pathogen countermeasures that serve to restrict the replication of pathogens early in infection. A successful innate response promotes the secretion of cytokines and growth factors that shape the later pathogen-specific, or acquired immune response composed of B- and T-lymphocytes. While the role of type I interferons in the clearance of infectious agents is unquestionable, their role in the immune system in the absence of microbial presence is substantially less well understood. We had previously reported a dramatic increase in susceptibility towards autoimmunity in mice lacking the interferon-activated STAT1 transcription factor. We recently discovered that IFN¿ produced by medullary thymic epithelial cells (mTEC) - a major source of IFN¿ in the thymus - acts in an autocrine feedback loop that appears to regulate mTEC maturation. Our most recent studies revealed a considerable contribution of the type I interferon system to the development of regulatory T cell that is likely to contribute to the development of various autoimmune disorders. We demonstrated a novel and critical involvement of IRFs and the type I interferon signaling system in the development and function of both natural and induced regulatory T cells which are crucial in the maintenance of peripheral tolerance and the prevention of autoimmunity. We therefore propose to investigate the unique functions of IRFs, IFN¿/¿ and STAT1 in the processes of Treg cell development and function. In Aim 1 we will investigate the role of STATs and IFN¿/¿ signaling components in the development of natural and induced Treg cells. We will determine whether T cell intrinsic requirements for these factors exist, or whether their impaired development results from an impaired thymic architecture. We will further investigate the mechanism why STAT1-deficient FoxP3+ cells fail to suppress effector T cells, and whether interferon can alter the conversion of conventional effector T cells into induced Treg cells. Our pilot experiments also revealed that IRF3-deficiency leads to increased natural Foxp3+ Treg cell numbers with progressive age. Unexpectedly, while natural Treg cells were increased in IRF3-/- mice, we observed a concomitant defect in the generation of induced (adaptive) Foxp3+ Treg cells. We noted that IRF3-/- natural Treg cells function normally, but strikingly, conventional IRF3-/- CD4+T cells are resistant to suppression by Treg cell. We will therefore determine in Aim 2 whether IRF3 is required in a T cell-intrinsic manner, and whether the failure of IRF3-deficient CD4+ T cells to respond to Treg cell-mediated suppression is due developmental alteration that occurred due to IRF3-deficiency in other thymic cell populations. The anticipated results will not only shed light onto a novel aspect of Treg cell development but also elucidate an additional biological role of type I interferons. Even though interferons are being used clinically to treat autoimmune diseases such as Multiple Sclerosis, the underlying mechanism is poorly understood. The proposed studies will extend our understanding of the contributions of IRFs and type I interferons in the development of Treg cells that are essential in the maintenance of self-tolerance.

描述（由适用提供）：先天免疫响应是一个古老的防御系统，由功能上不同的子系统组成，这些系统已进化为应对微生物病原体的感染。先天反应通常不是抗原特异性的，并且由干扰素（IFN）系统以及基于细胞的抗死病原体对策组成，这些对抗有助于限制感染早期病原体的复制。成功的先天反应促进了细胞因子和生长因子的秘密，这些因子塑造了后来的病原体特异性或获得的免疫反应，由B-和T淋巴细胞组成。虽然I型干扰在清除传染剂中的作用是毫无疑问的，但在没有微生物存在的情况下，它们在免疫系统中的作用尚不清楚。我们以前曾报道过缺乏干扰激活的STAT1转录因子的小鼠对自身免疫性的敏感性显着提高。我们最近发现，胸腺上皮细胞（MTEC）（胸腺中的IFN`的主要来源）起作用的IFN`起作用，它起作用的自分泌反馈环，似乎调节了MTEC成熟。我们最近的研究表明，I型干扰素系统对调节性T细胞开发的考虑贡献很可能有助于各种自身免疫性疾病的发展。我们证明了IRF的新颖而关键的参与以及I型干扰素信号系统在自然和诱导的调节性T细胞的开发和功能中，这对于维持外围耐受性和预防自身免疫至关重要。因此，我们建议在Treg细胞开发和功能的过程中研究IRF，IFN� /€和STAT1的独特功能。在AIM 1中，我们将研究统计数据和IFN� /€信号成分在自然和诱导Treg细胞发展中的作用。我们将确定T细胞对这些因素的内在需求是否存在，或者它们的发育受损是否导致胸腺结构受损。我们将进一步研究为什么STAT1缺陷FOXP3+细胞无法抑制效应T细胞的机制，以及干扰素是否可以改变常规效应T细胞转化为诱导的Treg细胞。我们的试点实验还表明，IRF3缺乏症会导致随着渐进式年龄的增加天然FOXP3+ Treg细胞数量。出乎意料的是，虽然在IRF3 - / - 小鼠中增加了天然Treg细胞，但我们观察到诱导（自适应）FOXP3+ Treg细胞的伴随缺陷。我们注意到IRF3 - / - 天然Treg细胞正常起作用，但引人注目的是，常规的IRF3 - / - CD4+T细胞对Treg细胞的抑制具有抗性。因此，我们将在AIM 2中确定是否需要以T细胞中的方式需要IRF3，以及IRF3缺乏CD4+ T细胞对Treg细胞介导的抑制的反应是否是由于其他胸腺细胞种群中IRF3缺乏症而发生的。预期的结果不仅会阐明Treg细胞发育的新方面，而且还阐明了I型干扰素的其他生物学作用。即使在临床上使用干扰素来治疗自身免疫性疾病，例如多发性硬化症，但对基本机制的了解很少。拟议的研究将扩展我们对IRF和I型干扰素在Treg细胞开发中的贡献的理解，这对于维持自我耐受至关重要。