中枢神经系统自身免疫的调节-猫眼课题宝

中枢神经系统自身免疫的调节

批准号：

10115575

负责人：

Francisco J. Quintana

金额：

$41.28万

依托单位：

BRIGHAM AND WOMEN'S HOSPITAL

依托单位国家：

美国

项目类别：

财政年份：

2017

资助国家：

美国

项目状态：

已结题

起止时间：

2017-02-02 至 2023-01-31

来源：

https://reporter.nih.gov/project-details/10115575

关键词：

Adenosine Adenosine Monophosphate Adenosine Triphosphate Agonist Aryl Hydrocarbon Receptor Autoimmune Diseases Biological Response Modifiers CD4 Positive T Lymphocytes CNS autoimmunity Cell Lineage Cell physiology Cells Code Data Dendritic Cells Disease Equilibrium Eragrostis Experimental Autoimmune Encephalomyelitis Gene Expression Genes Genetic Transcription Goals Human Hypoxia Hypoxia Inducible Factor Immune Immune response Immune system Impairment In Vitro Inflammasome Inflammatory Interleukin-10 Mediating Molecular Multiple Sclerosis Mus Pathway interactions Phenotype Play Production Receptor Activation Regulation Regulatory T-Lymphocyte Role Signal Transduction System T cell differentiation T-Cell Activation T-Lymphocyte Therapeutic Tissues autoimmune inflammation cytokine effector T cell extracellular immunoregulation in vivo multiple sclerosis patient novel novel therapeutics polarized cell programs targeted treatment therapeutic target tool transcription factor

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项目成果

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中文摘要

翻译

项目总结产生IL-10的1型调节性T细胞(TR1细胞)在免疫调节中起着重要作用回应。因此，TR1细胞是治疗炎症性疾病的潜在靶点，但人们对其知之甚少对它们的分化、稳定性和功能进行控制。我们发现转录因子芳香碳氢化合物受体(AHR)促进TR1细胞分化。AHR驱动TR1靶基因的表达细胞，例如编码CD39的Entpd1。CD39降解胞外三磷酸腺苷(EATP) 并合成免疫抑制的腺苷。我们现在发现：1)eATP与缺氧，其中表征炎症组织，抑制TR1细胞分化。2)eATP和缺氧激活缺氧- 诱导因子-1α(α)，抑制促肾上腺皮质激素释放激素驱动的基因表达。3)CD39在TR1细胞中的表达 (CD39Tr1)通过消耗eATP促进TR1细胞分化。4)CD39Tr1缺陷损伤TR1细胞分化抑制功能。5)树突状细胞(DCs，CD39DC)表达CD39促进TR1细胞分化。这些发现表明，CD39通过稳定AHR驱动的方式控制TR1细胞依赖的免疫调节基因表达。我们假设AHR/CD39和eATP/HIF1α之间的平衡控制Tr1 细胞。这个项目的目的是阐明这些新的通路在TR1细胞上的作用，以及它们的与多发性硬化症(MS)和其他自身免疫性疾病相关。我们的具体目标是：具体目标1：CD39Tr1在TR1细胞稳定性和功能中的作用是什么？ CD39Tr1缺陷损害了TR1细胞AHR驱动的基因表达和抑制功能。这些数据提示CD39Tr1通过消耗eATP，稳定了AHR驱动的TR1细胞的转录程序。因此，我们建议：1)确定CD39Tr1在实验性自身免疫过程中对TR1细胞稳定性的作用脑脊髓炎(EAE)。2)确定eATP和低氧对TR1细胞稳定性的影响及其调控 CD39Tr1.3)建立eATP和低氧对TR1细胞转录程序的影响。特定目标2：CD39Tr1能控制人TR1细胞吗？ AHR/CD39和eATP/HIF1α在人TR1细胞中的作用及其治疗潜力尚不清楚。因此，我们建议：1)建立AHR/CD39和eATP-HIF1/HIF1α在细胞分化中的作用。人TR1细胞。2)确定CD39 TR1细胞缺陷是否与MS有关。具体目标3：CD39DC如何控制TR1细胞？ CD39DC在体外可促进T细胞表达IL-10，抑制自身免疫性炎症。因此，我们建议目的：1)研究CD39DC在体内对TR1细胞的调控作用。2)确定eATP信号在T细胞中的作用 CD39DC对TR1细胞的调控作用。3)明确CD39DC对DC表型和功能的影响。总之，我们在老鼠和人类系统中使用独特的工具来研究控制TR1的新途径细胞，以及治疗多发性硬化症和其他自身免疫性疾病的潜在靶点。第2期

英文摘要

PROJECT SUMMARY IL-10 producing type 1 regulatory T cells (Tr1 cells) play an important role in controlling the immune response. Thus, Tr1 cells are potential targets for treating inflammatory disorders, but little is known about the control of their differentiation, stability and function. We have found that the transcription factor aryl hydrocarbon receptor (AHR) promotes Tr1 cell differentiation. AHR drives the expression of target genes in Tr1 cells, for example Entpd1 which codes for CD39. CD39 degrades extracellular adenosine triphosphate (eATP) and synthesizes immunosuppressive adenosine. We now found that: 1) eATP and hypoxia, which characterize inflamed tissues, inhibit Tr1 cell differentiation. 2) eATP and hypoxia activate the hypoxia- inducible factor-1α (HIF1α), which inhibits AHR-driven gene expression. 3) CD39 expressed in Tr1 cells (CD39Tr1) promotes Tr1 cell differentiation by depleting eATP. 4) CD39Tr1 deficiency impairs Tr1 cell differentiation and suppressive function. 5) CD39 expressed in DCs (CD39DC) promotes Tr1 cell differentiation. These findings suggest that CD39 controls Tr1 cell dependent immune regulation by stabilizing AHR-driven gene expression. We hypothesize that the balance between AHR/CD39 and eATP/HIF1α controls Tr1 cells. The objective of this project is to elucidate the role of these novel pathways on Tr1 cells, and their relevance for multiple sclerosis (MS) and other autoimmune diseases. Our specific aims are: Specific Aim 1: What is the role of CD39Tr1 in Tr1 cell stability and function? CD39Tr1 deficiency impairs AHR-driven gene expression and suppressive function in Tr1 cells. These data suggest that by depleting eATP, CD39Tr1 stabilizes the AHR-driven transcriptional program of Tr1 cells. Thus, we propose to: 1) Define the role of CD39Tr1 on Tr1 cell stability during experimental autoimmune encephalomyelitis (EAE). 2) Determine the effects of eATP and hypoxia on Tr1 cell stability and their control by CD39Tr1. 3) Establish the effects of eATP and hypoxia on the transcriptional program of Tr1 cells. Specific Aim 2: Does CD39Tr1 control human Tr1 cells? The roles of AHR/CD39 and eATP/HIF1α on human Tr1 cells and their therapeutic potential are unknown. Thus, we propose to: 1) Establish the roles of AHR/CD39 and eATP-Hypoxia/HIF1α on the differentiation of human Tr1 cells. 2) Determine whether deficits in CD39+ Tr1 cells are associated to MS. Specific Aim 3: How does CD39DC control Tr1 cells? CD39DC promotes IL-10 expression by T cells in vitro and limits autoimmune inflammation. Thus, we propose to: 1) Determine the role of CD39DC in controlling Tr1 cells in vivo. 2) Establish the role of eATP signaling in T cells on the control of Tr1 cells by CD39DC. 3) Define the effects of CD39DC on DC phenotype and function. IN SUMMARY, we use unique tools in mouse and human systems to study novel pathways that control Tr1 cells, as well as potential therapeutic targets for MS and other autoimmune diseases. 2

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