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.

项目概要 胸腺中自身抗原特异性 CD4+ Tregs 的编程对于抑制异常至关重要 免疫反应和预防自身免疫。 Tregs 还可以控制病毒感染期间的炎症， 病原体清除后。这对于某些类型的病毒感染尤其重要，例如 1918 年 流感大流行毒株，以及最近的冠状病毒的特定毒株，其中免疫反应 本身就可能致病。除了病毒感染外，高水平的 I 型干扰素也是某些疾病的一个决定性特征。 自身免疫性疾病，例如系统性红斑狼疮或干燥综合征； Tregs 可减轻此类自身免疫症状 疾病也是如此。然而，我们对参与上述任一过程的 Tregs 知之甚少。 例如，这些反应涉及哪些类型的 Tregs？ Tregs 会抑制抗病毒免疫吗 反应或抑制胸腺中类似系统性红斑狼疮的疾病的发展？如果是这样，控制的胸腺生态位是什么？ 这个Treg子集的分化？该 Treg 亚群的分化需要哪些 APC/基质细胞？ 该 Treg 亚群在病毒感染或 SLE 期间发挥什么具体功能作用？我们的初步数据 证明胸腺中发育着一个独特的 Tregs 子集，其特征是具有强大的 干扰素刺激基因特征（ISG-Tregs）。我们认为这个 ISG-Treg 子集起着关键作用 在控制抗病毒免疫反应和抑制自身免疫免疫反应中的作用 以高水平干扰素为特征的疾病。我们将在两个具体目标中探讨这一假设。在目标 1 中， 我们将确定胸腺中的 IFN 信号传导如何影响胸腺选择和 ISG-Treg 的发育。 在目标 2 中，我们将确定 ISG-Treg 响应病毒感染和系统性狼疮的功能 红斑病。成功完成这些目标将使我们能够确定 ISG- Tregs 产生于胸腺，决定 ISG-Treg 在病毒免疫反应中的作用，以及 与高水平干扰素相关的自身免疫性疾病，例如系统性红斑狼疮或干燥综合征。