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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.

项目概要多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 的自身免疫性疾病，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）作为动物模型女士。 Foxp3+ 调节性 T 细胞 (Treg) 是在健康个体中控制 CD4+ T 细胞的 T 细胞。在 MS 患者中，调节性 T 细胞不如健康个体那么有效，并且 CD4+ T 细胞具有效应/记忆表型并产生 IFN-g、IL-17 和 GM-CSF。尽管所采用的机制调节性 T 细胞控制幼稚 CD4+ T 细胞已被充分描述，但尚不清楚调节性 T 细胞如何 CNS自身免疫过程中控制体内效应/记忆Th1、Th17细胞。此外，是否 Th1、Th17 和 ThGM 细胞在 EAE 期间对 Treg 活性的影响尚未确定。使用缺乏细胞因子受体的小鼠中效应髓磷脂特异性 Th1 和 Th17 细胞的过继转移模型（调节性T细胞中的IL-6受体（IL-6R）或糖蛋白130（gp130），我们已经确定删除 Treg 中的 IL-6R 表达增强了其控制 Th17 细胞的能力，但不增强控制 Th1 细胞的能力。相比之下，缺乏 Treg 中的 gp130 会损害其抑制 Th1 的能力，但不会损害 Th17 介导的 EAE。在这个提案中，我们将解决 Treg 中 IL-6R 和 gp130 信号传导的调节是否影响其控制能力 ThGM 细胞。此外，使用一种新颖的鼠标线，可以跟踪和有条件地删除 GM-CSF+ T 细胞，我们将讨论在 EAE 进展过程中删除 GM-CSF+ T 细胞是否可以影响Treg功能和病程。我们的实验将共同进一步确定 Th1、Th17 和 ThGM 细胞在 EAE 过程中对 Treg 的活性有不同的影响。该提案的完成也可能带来基于 MS 和 EAE 异质性以及抑制减弱的基础的新见解 Treg 在 EAE 和 MS 中的活性。