Mechanisms of suppression of effector T cells in EAE

项目摘要 多发性硬化症（MS）是中枢神经系统（CNS）的自身免疫性疾病，其由 髓磷脂反应性效应T细胞。实验性自身免疫性脑脊髓炎（EAE）作为动物模型 Foxp 3+调节性T细胞（Treg）是在健康个体中保持CD 4 + T细胞处于检查中的T细胞。在 在MS患者中，调节性T细胞不像健康个体那样有效，并且CD 4 + T细胞在MS患者中具有免疫调节作用。 效应子/记忆表型并产生IFN-γ、IL-17和GM-CSF。尽管这些机制 调节性T细胞控制幼稚的CD 4 + T细胞已经有了很好的描述，但目前尚不清楚调节性T细胞是如何控制幼稚的CD 4 + T细胞的。 在CNS自身免疫过程中控制体内效应/记忆Th 1、Th 17细胞。此外，无论 Th 1、Th 17和ThGM细胞在EAE期间对Treg活性的差异影响尚未确定。使用 缺乏细胞因子受体的小鼠中效应髓鞘特异性Th 1和Th 17细胞的过继转移模型 (IL-6受体（IL-6 R）或糖蛋白130（gp 130）的缺失，我们已经确定， Treg中的IL-6 R表达增强了它们控制Th 17细胞而不是Th 1细胞的能力。相反，缺乏 Treg中的gp 130损害了它们抑制Th 1介导的EAE而不是Th 17介导的EAE的能力。在本提案中，我们 将解决调节性T细胞中IL-6 R和gp 130信号传导是否影响其控制 ThGM细胞此外，使用一种新颖的鼠标线，允许跟踪和有条件删除 GM-CSF+ T细胞，我们将讨论在EAE进展过程中GM-CSF+ T细胞的缺失是否可以 影响Treg功能和疾病进程。总之，我们的实验将进一步确定Th 1，Th 17和 ThGM细胞在EAE期间差异性地影响Treg的活性。这项提案的完成也可能带来 对MS和EAE异质性的基础以及对抑制性降低的基础的新认识 EAE和MS中Treg的活性。

Project Summary Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) which is mediated by myelin reactive effector T cells. Experimental autoimmune encephalomyelitis (EAE) serves as an animal model of MS. Foxp3+ regulatory T cells (Treg) are T cells which, in healthy individuals, keep CD4+ T cells in check. In MS patients, regulatory T cells are not as effective as in healthy individuals, and CD4+ T cells have an effector/memory phenotype and produce IFN-g, IL-17 and GM-CSF. Although the mechanisms by which regulatory T cells control naïve CD4+ T cells have been well described, it is not known how regulatory T cells control effector /memory Th1, Th17 cells in vivo during the course of CNS autoimmunity. In addition, whether Th1, Th17 and ThGM cells differentially affect the activity of Treg during EAE has not been determined. Using an adoptive transfer model of effector myelin specific Th1 and Th17 cells in mice lacking cytokine receptors (IL-6 receptor (IL-6R) or the glycoprotein 130 (gp130) in regulatory T cells, we have established that deletion of IL-6R expression in Treg enhances their capacity to control Th17 but not Th1 cells. In contrast, the lack of gp130 in Treg compromises their capacity to suppress Th1 but not Th17 mediated EAE. In this proposal, we will address whether the modulation of IL-6R and gp130 signaling in Treg affects their capacity to control ThGM cells. In addition, using a novel mouse line that allows for the tracking and the conditional deletion of GM-CSF+ T cells, we will address whether the deletion of GM-CSF+ T cells during the progression of EAE can affect Treg functions and disease course. Together, our experiments will further establish how Th1, Th17 and ThGM cells differentially affect the activity of Treg during EAE. The completion of this proposal might also bring new insight on the basis for MS and EAE heterogeneity and on the foundations for the diminished suppressive activity of Treg in EAE and MS.