Regulation of pathogenic T cells in EAE

项目总结/摘要 多发性硬化症（MS）是一种慢性自身免疫性疾病，其特征在于炎症， 中枢神经系统（CNS）的脱髓鞘。这导致进行性神经功能障碍， 身体损伤自身反应性CD 4 + T细胞在MS的发生和发展中起重要作用 及其小鼠模型（实验性自身免疫性脑脊髓炎，EAE）。产生IL-17、IFN-g和GM-CSF的T细胞 CSF（Th 17、Th 1和ThGM-CSF）均已显示在免疫致病性中起重要作用。 MS和EAE。虽然，目前 几种疾病修饰疗法（DMT），可减少MS 症状，目前还没有治愈这种疾病。 信号转导和转录激活因子（STAT 1）是一种有效的基因表达调节因子， 对I、II和III型干扰素和IL-27的应答，而且对细胞增殖、生长和 迁移因此，STAT 1的消除具有限制致病性T细胞的产生和/或致病性T细胞的潜力。 然而，这种可能性从未在EAE的背景下使用适当的工具进行过正式调查。 在这里，我们首次表明，STAT 1条件性缺失T细胞废除EAE的发展。不 来自这些小鼠的细胞可以分化为Th 1和Th 17细胞，但不能在CNS中积累， EAE。此外，STAT 1条件性缺失的T细胞产生更多的IL-10，并具有更多的调节性T细胞。 细胞 STAT 1缺陷小鼠发生加重的EAE，突出了STAT 1介导的保护作用 EAE发展中的信号传导。然而，负责STAT 1的细胞类型和分子途径 对EAE的保护作用尚未阐明。使用选择性删除小胶质细胞中的STAT 1，我们有 小胶质细胞中的STAT 1信号是保护性的。 这些新的数据表明，限制T细胞中的STAT 1信号传导和维持T细胞中的STAT 1信号传导是可能的。 小胶质细胞可用于限制CNS自身免疫的发展和进展。 这里将要检验的假设是，在细胞中，STAT 1下游的不同关键调节机制是通过调节细胞内的细胞因子来实现的。 可以利用特定的细胞类型来限制CNS自身免疫的发展。具体而言，我们建议： 目标1。为了研究STAT 1的缺失限制所有致病性细胞亚群的潜在机制， T细胞。 目标二。研究STAT 1如何调控T细胞活性。 目标3。目的：探讨STAT 1限制先天性细胞功能和EAE发生的机制。

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.