Development of Immune Tolerance

免疫耐受的发展

• 批准号: 10338131
• 负责人: Michael Archibald Farrar
• 金额: $ 46.01万
• 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/10338131
• 关键词: Affect; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Bacteria; Biology; Cells; Complex; Coronavirus; 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; Interferon-beta; Interferons; LoxP-flanked allele; Lupus; Mediating; Modeling; Mus; Organism; Pathogenicity; Pathology; Peptides; Play; Prevention; Process; 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 Receptor Genes; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Tissues; Up-Regulation; Viral; Virus; Virus Diseases; cell type; genetic signature; in vivo; influenza infection; migration; mouse model; novel; pandemic influenza; pathogen; prevent; progenitor; programs; reduce symptoms; response; secondary lymphoid organ; single-cell RNA sequencing; 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.

项目摘要 胸腺中自身抗原特异性CD 4 + T细胞的程序化对于抑制异常免疫应答是必需的。 免疫应答和自身免疫的预防。在病毒感染期间，Tactinase还控制炎症， 病原体清除后。这对于某些类型的病毒感染特别相关，例如1918年的 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 本身就可能是致病的。除了病毒感染外，高水平的I型IFN是某些肿瘤的定义特征。 自身免疫性疾病，如SLE或舍格伦综合征; TdR减少这种自身免疫性疾病的症状 疾病也是。然而，我们对上述两个过程中涉及的TdR知之甚少。 例如，在这些反应中涉及哪些类型的T细胞？抑制抗病毒免疫力的激素 反应或抑制SLE样疾病在胸腺中的发展？如果是的话，控制着 这个Treg亚群的分化？这种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期间发挥什么特定的功能作用？我们的初步数据 证明了一个独特的亚群TcR在胸腺中发育，其特征是强烈的 干扰素刺激的基因签名（ISG-THEB）。我们认为，ISG-Treg亚群在免疫调节中起着关键作用。 在控制抗病毒免疫应答和抑制自身免疫应答中的作用 以高水平IFN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-T细胞的发育。 在目标2中，我们将确定ISG-TdR在病毒感染和系统性狼疮中的功能 尿道炎成功完成这些目标将使我们能够确定ISG- T细胞在胸腺中产生，并决定ISG-T细胞在对病毒的免疫应答中的作用， 与高水平IFN相关的自身免疫性疾病，如SLE或干燥综合征。