Mechanisms of suppression of effector T cells in EAE

EAE 中效应 T 细胞的抑制机制

基本信息

批准号：
9916611
负责人：
Estelle Bettelli
金额：
$ 25.67万
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：
2020
资助国家：
美国
起止时间：
2020-01-21 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916611
关键词：
Ablation Address Adoptive Transfer Affect Animal Model Autoimmune Process Autoimmune Responses Autoimmunity Automobile Driving Biological Models CD4 Positive T Lymphocytes CNS autoimmune disease CNS autoimmunity Cells Central Nervous System Diseases Cytokine Receptors Cytokine Signaling Data Demyelinations Development Disease Disease Progression Experimental Autoimmune Encephalomyelitis FOXP3 gene Foundations Geography Granulocyte-Macrophage Colony-Stimulating Factor Heterogeneity Human IL6 gene IL6ST gene Individual Inflammation Inflammatory Interferon Type II Interleukin 6 Receptor Interleukin-12 Interleukin-17 Interleukin-6 Location Mediating Memory Modeling Motor Multiple Sclerosis Mus Myelin Neurodegenerative Disorders Phase Phenotype Play Population Regulation Regulatory T-Lymphocyte Role Signal Pathway Signal Transduction T cell differentiation T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Transforming Growth Factor beta autoreactivity cytokine effector T cell experimental study glycoprotein 130 in vivo insight interleukin-23 memory CD4 T lymphocyte mouse model multiple sclerosis patient novel receptor receptor expression recruit response tool

项目摘要

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.

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，该疾病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）用作动物模型 MS。 FOXP3+调节性T细胞（TREG）是T细胞，在健康个体中，CD4+ T细胞受检查。在 MS患者，调节性T细胞在健康个体中不如健康个体，CD4+ T细胞具有效应子/记忆表型并产生IFN-G，IL-17和GM-CSF。虽然所采用的机制调节性T细胞控制着幼稚的CD4+ T细胞，已经很好地描述了调节性T细胞如何在CNS自身免疫过程中，控制效应子 /记忆TH1，体内Th17细胞。另外，是否尚未确定TH1，TH17和THGM细胞对EAE期间Treg的活性有所不同。使用缺乏细胞因子受体的小鼠的效应髓磷脂特异性Th1和Th17细胞的自适应转移模型（IL-6受体（IL-6R）或调节T细胞中的糖蛋白130（GP130），我们已经确定了这种缺失 TREG中的IL-6R表达增强了他们控制Th17而不是TH1细胞的能力。相反，缺乏 Treg中的GP130损害了他们抑制Th1但没有Th17介导的EAE的能力。在这个建议中，我们将解决Treg中IL-6R和GP130信号的调制是否影响其控制能力 thgm细胞。另外，使用新型鼠标线，允许跟踪和条件删除 GM-CSF+ T细胞，我们将解决EAE进展过程中GM-CSF+ T细胞的缺失是否可以影响Treg功能和疾病过程。我们的实验将共同确定TH1，TH17和 THGM细胞对EAE期间Treg的活性有所不同。该提案的完成也可能带来基于MS和EAE异质性的新见解以及抑制作用减少的基础 Treg在EAE和MS中的活动。