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: 8607894
• 负责人: MICHAEL DAVID
• 金额: $ 22.07万
• 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/8607894
• 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; Interferon Type II; 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（由申请人提供）：先天免疫反应是一种古老的防御系统，由功能不同的子系统组成，这些子系统已经进化为对抗微生物病原体的感染。先天性应答通常不是抗原特异性的，并且由干扰素（IFN）系统以及用于在感染早期限制病原体复制的基于细胞的抗病原体对策组成。成功的先天性应答促进细胞因子和生长因子的分泌，所述细胞因子和生长因子形成由B淋巴细胞和T淋巴细胞组成的后来的病原体特异性或获得性免疫应答。虽然I型干扰素在清除感染因子中的作用是毋庸置疑的，但在微生物不存在的情况下，它们在免疫系统中的作用基本上不太清楚。我们以前曾报道过，在缺乏干扰素激活的STAT 1转录因子的小鼠中，对自身免疫的易感性显著增加。我们最近发现，由胸腺髓质上皮细胞（mTEC）产生的IFN <$-胸腺中IFN <$的主要来源-在自分泌反馈回路中起作用，该回路似乎调节mTEC成熟。我们最近的研究揭示了I型干扰素系统对调节性T细胞的发展的相当大的贡献，这可能有助于各种自身免疫性疾病的发展。 我们证明了IRFs和I型干扰素信号传导系统在天然和诱导的调节性T细胞的发育和功能中的新颖和关键参与，这些调节性T细胞在维持外周耐受和预防自身免疫中至关重要。因此，我们建议研究IRFs，IFN <$/<$和STAT 1在Treg细胞发育和功能过程中的独特功能。 在目标1中，我们将研究STAT和IFN <$/<$信号传导组分在天然和诱导Treg细胞发育中的作用。我们将确定是否存在T细胞对这些因子的内在需求，或者它们受损的发育是否是由受损的胸腺结构引起的。我们将进一步研究STAT 1缺陷型FoxP 3+细胞不能抑制效应T细胞的机制，以及干扰素是否可以改变传统效应T细胞向诱导Treg细胞的转化。 我们的初步实验还显示，IRF 3缺陷导致随着年龄的增长自然Foxp 3 + Treg细胞数量增加。出乎意料的是，虽然天然Treg细胞在IRF 3-/-小鼠中增加，但我们观察到诱导（适应性）Foxp 3 + Treg细胞产生的伴随缺陷。我们注意到IRF 3-/-天然Treg细胞功能正常，但引人注目的是，常规IRF 3-/-CD 4 +T细胞对Treg细胞的抑制具有抗性。因此，我们将在目标2中确定IRF 3是否以T细胞内在方式需要，以及IRF 3缺陷型CD 4 + T细胞对Treg细胞介导的抑制反应的失败是否是由于其他胸腺细胞群中由于IRF 3缺陷而发生的发育改变。 预期的结果不仅将揭示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。尽管干扰素在临床上被用于治疗自身免疫性疾病，如多发性硬化症，但其潜在机制仍知之甚少。拟议的研究将扩大我们的理解的贡献IRFs和I型干扰素在发展中的调节性T细胞是必不可少的自我耐受性的维护。