Regulation of pathogenic T cells in EAE

EAE 中致病性 T 细胞的调节

基本信息

批准号：
10058806
负责人：
Estelle Bettelli
金额：
$ 42.88万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058806
关键词：
CD4 Positive T Lymphocytes CNS autoimmunity Cell Proliferation Cell physiology Cells Data Demyelinations Development Disease Experimental Autoimmune Encephalomyelitis Gene Expression Generations Granulocyte-Macrophage Colony-Stimulating Factor Growth Immune Impairment Inflammation Interferon Type II Interferons Interleukin-10 Interleukin-17 Mediating Mediator of activation protein Microglia Molecular Multiple Sclerosis Mus Neuraxis Neurologic Dysfunctions Pathogenicity Pathologic Pathway interactions Patients Play Regulation Regulator Genes Regulatory T-Lymphocyte Role STAT protein Signal Transduction Symptoms System T cell response T-Lymphocyte Testing Time Tissues Transcriptional Regulation Tumor-infiltrating immune cells autoreactivity cell type chronic autoimmune disease cytokine cytotoxic environmental change gain of function migration mouse model multiple sclerosis patient multiple sclerosis treatment novel protective effect response tool trafficking

项目摘要

Project Summary/Abstract Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation and demyelination of the central nervous system (CNS). This results in progressive neurological dysfunction and physical impairment. Auto-reactive CD4+ T cells play an important role in the initiation and progression of MS and its mouse model (experimental autoimmune encephalomyelitis, EAE). T cell producing IL-17, IFN-g and GM- CSF (Th17, Th1 and ThGM-CSF) have all been shown to play an important role in the immunopathogenicity of MS and EAE. Although, there are currently several disease modifying therapies (DMT), which reduce MS symptoms, there is not yet a cure for this disease. Signal transducers and activators of transcription (STAT1) is a potent regulator of gene expression in response to type I, II and III interferon and IL-27 but also has profound effect on cell proliferation, growth and migration. Therefore, elimination of STAT1 has the potential to limit the generation and/or of pathogenic T cells. However, this possibility had never been formally investigated in the context of EAE with the appropriate tools. Here, we show for the first time that STAT1 conditional deletion in T cells abrogates the development of EAE. T cells from these mice can differentiate in Th1 and Th17 cells but fail to accumulate in the CNS and do not cause EAE. Furthermore, T cells with a conditional deletion of STAT1 produce more IL-10 and have more regulatory T cells. STAT1 deficient mice develop exacerbated EAE, highlighting a protective role of STAT1 mediated signaling in EAE development. However, the cell type(s) and molecular pathways responsible for STAT1 protective effect in EAE have not been delineated. Using a selective deletion of STAT1 in microglia, we have established that STAT1 signaling in microglia is protective. These novel data suggest that limitation of STAT1 signaling in T cells and sustain STAT1 signaling in microglia could be exploited to limit the development and progression of CNS autoimmunity. The hypothesis that will be tested here is that different key regulatory mechanisms downstream of STAT1 in specific cell types can be exploited to limit the development of CNS autoimmunity. Specifically, we propose: Aim 1. To investigate the underlying mechanism by which the absence of STAT1 limits all subsets of pathogenic T cells. Aim 2. To study how STAT1 controls regulatory T cell activity. Aim 3. To determine the mechanisms by which STAT1 limit innate cell functions and the development of EAE.

项目摘要/摘要多发性硬化症（MS）是一种慢性自身免疫性疾病，其特征是炎症和中枢神经系统（CNS）的脱髓鞘。这会导致进行性神经功能障碍和身体障碍。自动反应性CD4+ T细胞在MS的启动和进展中起重要作用及其小鼠模型（实验性自身免疫性脑脊髓炎，EAE）。产生IL-17的T细胞，IFN-G和GM- CSF（TH17，TH1和THGM-CSF）均已证明在免疫原性中起重要作用 MS和EAE。虽然，目前有几种疾病修饰疗法（DMT），可减少MS 症状，尚未治愈这种疾病。转录的信号换能器和激活因子（STAT1）是基因表达的有效调节剂对I型，II和III型干扰素和IL-27的反应，但对细胞增殖，生长和迁移。因此，消除STAT1有可能限制致病性T细胞的产生和/或。但是，这种可能性从未在EAE的背景下使用适当的工具进行正式研究。在这里，我们首次表明T细胞中的STAT1条件缺失消除了EAE的发展。 t 这些小鼠的细胞可以在Th1和Th17细胞中区分，但无法在中枢神经系统中积聚，不会引起伊。此外，具有条件缺失STAT1的T细胞产生更多的IL-10，并且具有更多的调节t 细胞。 STAT1缺乏小鼠会发出恶化的EAE，强调了STAT1介导的保护作用 EAE开发中的信号传导。但是，造成STAT1的细胞类型和分子途径 EAE中的保护作用尚未划定。使用小胶质细胞中STAT1的选择性删除，我们有确定小胶质细胞中的STAT1信号是保护性的。这些新的数据表明，T细胞中STAT1信号的限制并维持在STAT1信号中可以利用小胶质细胞来限制CNS自身免疫性的发展和进展。这里将要检验的假设是STAT1下游的不同关键调节机制可以利用特定的细胞类型来限制CNS自身免疫的发展。具体来说，我们建议：目的1。调查缺乏STAT1限制所有致病子集的潜在机制 T细胞。目的2。研究STAT1如何控制调节性T细胞活性。目的3。确定STAT1限制先天细胞功能和EAE的发展的机制。