Development of Immune Tolerance

免疫耐受的发展

• 批准号: 10573296
• 负责人: Michael Archibald Farrar
• 金额: $ 45.37万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573296
• 关键词: 1918 influenza pandemic; Affect; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Bacteria; Cell physiology; Cells; Cellular biology; Complex; Coronavirus; Cytoprotection; Data; Dendritic Cells; Development; Disease; FOXP3 gene; Funding; Gene Expression; Genes; Grant; Hybridomas; IL2RA gene; Imiquimod; Immune; Immune Tolerance; Immune response; Infectious Agent; Inflammation; Influenza; Interferon Type I; Interferons; LoxP-flanked allele; Lupus; Mediating; Modeling; Mus; Organism; Pathogenicity; Pathology; Peptides; Play; Prevention; Process; Regulator Genes; Regulatory T-Lymphocyte; Role; STAT1 gene; Signal Transduction; Sjogren' s Syndrome; Source; Specificity; Stromal Cells; Structure of parenchyma of lung; Systemic Lupus Erythematosus; T-Cell Development; T-Cell Receptor Genes; T-Lymphocyte; T-Lymphocyte Subsets; TYRP1 gene; Testing; Thymic epithelial cell; Thymus Gland; Tissues; Up-Regulation; Viral; Virus; Virus Diseases; Visualization; cell type; genetic signature; in vivo; influenza infection; interferon alpha receptor; migration; mouse model; novel; pandemic influenza; pathogen; prevent; progenitor; programs; reduce symptoms; response; secondary lymphoid organ; single-cell RNA sequencing; stem cells; transcriptomics

PROJECT SUMMARY Programming of self-antigen specific CD4+ Tregs in the thymus is essential for suppression of aberrant immune responses and prevention of autoimmunity. Tregs also control inflammation during viral infection and following pathogen clearance. This is particularly relevant for some types of viral infections such as the 1918 influenza pandemic strain, and more recently, specific strains of coronaviruses, where the immune response itself can be pathogenic. In addition to viral infections, high levels of type I IFN are a defining feature of some autoimmune diseases, such as SLE or Sjögren’s syndrome; Tregs reduce the symptoms of such autoimmune diseases as well. However, we know relatively little about the Tregs involved in either of the above processes. For example, what types of Tregs are involved in these responses? Do Tregs that dampen anti-viral immune responses or suppress SLE-like disease develop in the thymus? If so, what is the thymic niche that controls differentiation of this Treg subset? What APCs/stromal cells are required for differentiation of this Treg subset? What specific functional roles does this Treg subset play during viral infections or SLE? Our preliminary data demonstrate that a unique subset of Tregs develops in the thymus characterized by a strong interferon-stimulated gene-signature (ISG-Tregs). We propose that this ISG-Treg subset plays a key role in governing antiviral immune responses and suppressing immune responses to autoimmune diseases characterized by high levels of IFN. We will explore this hypothesis in two specific aims. In aim 1, we will determine how IFN signaling in the thymus affects thymic selection and the development of ISG-Tregs. In aim 2, we will determine the functions of ISG-Tregs in response to viral infections and systemic lupus erythematosis. Successful completion of these aims will allow us to identify the mechanism by which ISG- Tregs arise in the thymus, and determine the role of ISG-Tregs in immune responses to viruses, and in autoimmune diseases associated with high levels of IFN, such as SLE or Sjögren’s syndrome.

项目总结 胸腺中自身抗原特异性的CD4+Tregs的编程对于抑制异常是必不可少的 免疫反应和自身免疫的预防。Treg还控制病毒感染期间的炎症和 在病原体清除后。这与某些类型的病毒感染特别相关，例如1918年 流感大流行毒株，以及最近出现的冠状病毒特定毒株，其免疫反应 它本身可能是致病的。除了病毒感染，高水平的I型干扰素是一些 自身免疫性疾病，如SLE或Sjögren综合征；Tregs可减轻这种自身免疫性疾病的症状 疾病也是如此。然而，我们对上述过程中涉及的特雷格人知之甚少。 例如，这些反应涉及哪些类型的Treg？抑制抗病毒免疫的树状细胞 反应或抑制类SLE疾病发生在胸腺？如果是这样，控制胸腺的利基是什么 这个Treg子集的区别吗？这个Treg亚群的分化需要哪些APC/基质细胞？ 这个Treg亚群在病毒感染或SLE中扮演着什么特定的功能角色？我们的初步数据 证明在胸腺中发育出一个独特的Tregs子集，其特征是 干扰素刺激基因签名(ISG-Tregs)。我们认为这个ISG-Treg子集起着关键作用 在调控抗病毒免疫应答和抑制自身免疫应答中的作用 以高水平干扰素为特征的疾病。我们将从两个具体目标来探讨这一假说。在目标1中， 我们将确定胸腺中的干扰素信号如何影响胸腺选择和ISG-Tregs的发育。 在目标2中，我们将确定ISG-Tregs在应对病毒感染和系统性红斑狼疮中的功能 红斑病。这些目标的成功实现将使我们能够确定国际支持小组-- Tregs产生于胸腺，决定了ISG-Tregs在对病毒的免疫反应中的作用，以及在 与高水平干扰素相关的自身免疫性疾病，如系统性红斑狼疮或干燥综合征。