Mechanisms of suppression of effector T cells in EAE

项目摘要 多发性硬化症(MS)是一种中枢神经系统(CNS)自身免疫性疾病，由 髓鞘反应性效应T细胞。实验性自身免疫性脑脊髓炎的动物模型 在女性中，Foxp3+调节性T细胞(Treg)是T细胞，在健康人中，它可以控制CD4+T细胞。在……里面 多发性硬化症患者，调节性T细胞不如健康人有效，而CD4+T细胞有 效应/记忆表型，产生干扰素-γ、白介素17和粒-巨噬细胞集落刺激因子。尽管通过这些机制 调节性T细胞控制幼稚的CD4+T细胞已经有了很好的描述，但尚不清楚调节性T细胞是如何 中枢神经系统自身免疫过程中体内调控效应/记忆Th1、Th17细胞。此外，是否 Th1、Th17和ThGM细胞在EAE过程中对Treg活性的不同影响尚未确定。vbl.使用 缺乏细胞因子受体的效应性髓鞘特异性Th1和Th17细胞过继转移模型 (IL-6受体(IL-6R)或调节性T细胞中的糖蛋白130(Gp130))，我们已经确定缺失 IL-6R在Treg中的表达增强了他们控制Th17细胞的能力，但不能控制Th1细胞。相比之下，缺乏 Treg中的gp130抑制Th1的能力，但不影响Th17介导的EAE。在这项提案中，我们 我将讨论IL-6R和gp130信号在Treg中的调制是否影响它们的控制能力 ThGM细胞。此外，使用一种新的鼠标行，允许跟踪和有条件删除 GM-CSF+T细胞，我们将解决在EAE进展过程中GM-CSF+T细胞的缺失是否可以 影响Treg功能和病程。我们的实验将进一步确定Th1、Th17和Th1是如何 ThGM细胞在EAE过程中对Treg的活性有不同程度的影响。这项提议的完成也可能带来 MS和EAE异质性的基础以及抑制减弱的基础的新见解 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.