Effector Function of Regulatory T Cells in EAE

EAE 中调节性 T 细胞的效应功能

• 批准号: 9470744
• 负责人: Mohamed Oukka
• 金额: $ 28.25万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9470744
• 关键词: Address; Apoptosis; Attention; Autoimmune Diseases; Autoimmunity; BACH2 gene; Blood Circulation; CD4 Positive T Lymphocytes; CD44 gene; Cells; Data; Development; Disease; Effector Cell; Endothelial Cells; Experimental Autoimmune Encephalomyelitis; FOXO1A gene; Homeostasis; Homing; Human; IL2RA gene; Immune; Immune system; Immunosuppressive Agents; Inflammation; Inflammatory Response; Interferon-beta; Lesion; Lipids; Lymphocyte; Lymphoid; Mediating; Memory; Modeling; Molecular; Multiple Sclerosis; Mus; Neuraxis; Oral; Organ; Patients; Pharmaceutical Preparations; Phase; Phenotype; Play; Population; Recovery; Regulatory T-Lymphocyte; Relapse; Role; SELL gene; SOX4 gene; Second Messenger Systems; Secondary to; Self Tolerance; Signal Transduction; Site; Sphingosine-1-Phosphate Receptor; T-Lymphocyte; Thymectomy; Thymus Gland; Tissue-Specific Gene Expression; Tissues; analog; base; immunoregulation; interest; migration; multiple sclerosis patient; patient subsets; receptor; response; sphingosine 1-phosphate; systemic autoimmunity; trafficking; transcription factor

Project Abstract The class of regulatory T cells that has gained the most attention is called CD4+CD25+ regulatory T cells. This class of regulatory T cells is generated in the thymus. Tregs leaving the thymus are a homogenous population of CD44loCD62LhiCCR7+ cells that preferentially migrate to secondary lymphoid organs. Consistent with their self-reactivity, upon entering the periphery, a subset of Tregs acquire an activated phenotype, upregulating expression of CD44 and other homing receptors that allow them to access non-lymphoid tissues. This proper distribution of Tregs is fundamental for their ability to maintain tolerance, suggesting a model whereby distinct Tregs subsets are specialized for functioning either within secondary lymphoid organs to inhibit T cell priming, or in specific non-lymphoid tissues and sites of inflammation to dampen effector cell responses. Expression of CD44 and CD62L can be used to define “central” TR (cTregs) and “effector” Tregs (eTregs) that differentially localize to lymphoid and non-lymphoid tissues respectively. Overall, the activation of eTregs leads to their expansion into highly suppressive, but short-lived cells well-suited to regulating inflammatory responses in non- lymphoid tissues. Sphingosine-1-phosphate (S1P) is a bioactive lipid with important functions in the immune system. The marked difference in S1P concentrations between the circulation and tissues constitutes the S1P gradient that drives the trafficking of various immune cells. Recently, S1P and S1P receptors have been specifically targeted as treatments for immune-mediated diseases, particularly the immunosuppressant FTY720 (Fingolimod Gilenya), an S1P analogue that has recently become the first oral therapy for relapsing Multiple Sclerosis. In MS patients, FTY720 effectively decreases relapse rates better than interferon Beta therapy; however, a subset of patients treated with FTY720 develop very severe relapses and even tumorfactive lesions. This finding suggests that S1P1-mediated signaling may be involved in some unknown immune regulation, in addition to its role in T trafficking. To address the specific role of S1P on Tregs, we have generated mice that lack S1P1 only in Tregs. Surprisingly, S1P1 Treg-deficient mice developed rapid and severe systemic autoimmunity, revealing a critical role of S1P for the function of Tregs. Interestingly, most Tregs found in S1P1 Treg-deficient mice are eTregs, which are more prone to die of apoptosis. The analysis of Tregs derived from MS patients treated with Gilenya or other oral drugs, such as Tecfidera, has revealed a dramatic change in Treg homeostasis and an increase in the number of eTregs only in patients treated with Gilenya. Based on our preliminary data, we hypothesized that S1P1-mediated signaling regulates the function of Tregs by inhibiting their differentiation into short-lived eTregs. In this study we propose to elucidate how S1P1-mediated signaling regulates the differentiation of eTregs.

项目摘要 最受关注的一类调节性 T 细胞称为 CD4+CD25+ 调节性 T 细胞。这 一类调节性 T 细胞是在胸腺中产生的。离开胸腺的 Tregs 是同质群体 CD44loCD62LhiCCR7+细胞优先迁移至次级淋巴器官。符合他们的 自我反应性，进入外周后，一部分 Tregs 获得激活的表型，上调 CD44 和其他归巢受体的表达使它们能够进入非淋巴组织。这个适当的 Tregs 的分布对于其维持耐受性的能力至关重要，这表明了一种模型，其中不同的 Tregs 亚群专门用于在次级淋巴器官内发挥作用，抑制 T 细胞启动， 或在特定的非淋巴组织和炎症部位，以抑制效应细胞反应。表达 CD44 和 CD62L 可用于定义“中枢”TR (cTreg) 和“效应”Treg (eTreg) 分别定位于淋巴组织和非淋巴组织。总体而言，eTreg 的激活导致其 扩展到高度抑制性但寿命短的细胞，非常适合调节非炎症反应 淋巴组织。 1-磷酸鞘氨醇 (S1P) 是一种生物活性脂质，在免疫中具有重要功能 系统。循环系统和组织之间 S1P 浓度的显着差异构成了 S1P 驱动各种免疫细胞运输的梯度。最近，S1P和S1P受体已被 专门针对免疫介导疾病的治疗，特别是免疫抑制剂 FTY720 （芬戈莫德 Gilenya），一种 S1P 类似物，最近成为第一个治疗复发性多发性硬化症的口服疗法 硬化。在 MS 患者中，FTY720 比干扰素 Beta 疗法更能有效降低复发率； 然而，接受 FTY720 治疗的一部分患者出现非常严重的复发，甚至肿瘤性病变。 这一发现表明 S1P1 介导的信号传导可能参与一些未知的免疫调节， 除了它在 T 贩运中的作用之外。为了解决 S1P 对 Tregs 的特定作用，我们培育了具有以下特征的小鼠： 仅在 Tregs 中缺乏 S1P1。令人惊讶的是，S1P1 Treg 缺陷小鼠出现了快速且严重的全身性疾病 自身免疫，揭示了 S1P 对 Tregs 功能的关键作用。有趣的是，大多数 Tregs 存在于 S1P1 中 Treg 缺陷的小鼠是 eTreg，更容易死于细胞凋亡。对Tregs的分析源自 使用 Gilenya 或其他口服药物（例如 Tecfidera）治疗的多发性硬化症患者的 Treg 细胞发生了巨大变化 仅在接受 Gilenya 治疗的患者中，体内稳态和 eTreg 数量增加。基于我们的 根据初步数据，我们假设 S1P1 介导的信号通过抑制 它们分化为短命的 eTreg。在这项研究中，我们打算阐明 S1P1 介导的信号传导如何 调节 eTreg 的分化。