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

项目摘要产生IL-10的1型调节性T细胞（Tr 1细胞）在控制免疫应答中起重要作用。反应因此，Tr 1细胞是治疗炎症性疾病的潜在靶点，但关于Tr 1细胞的作用机制知之甚少。控制其分化、稳定性和功能。我们发现转录因子aryl 碳氢化合物受体（AHR）促进Tr 1细胞分化。AHR驱动Tr 1中靶基因的表达细胞，例如编码CD 39的Entpd 1。CD 39降解细胞外三磷酸腺苷（eATP）并合成免疫抑制腺苷。我们现在发现：1）eATP和缺氧，表征发炎组织，抑制Tr 1细胞分化。2)eATP和缺氧激活缺氧- 诱导因子-1 α（HIF 1 α），抑制AHR驱动的基因表达。3)Tr 1细胞中表达的CD 39 （CD 39 Tr 1）通过消耗eATP促进Tr 1细胞分化。4)CD 39 Tr 1缺陷损害Tr 1细胞分化和抑制功能。5)DC中表达的CD 39（CD 39 DC）促进Tr 1细胞分化。这些发现表明，CD 39通过稳定AHR驱动的免疫调节来控制Tr 1细胞依赖性免疫调节。基因表达我们假设AHR/CD 39和eATP/HIF 1 α之间的平衡控制Tr 1 细胞本项目的目的是阐明这些新途径对Tr 1细胞的作用，以及它们对细胞增殖的影响。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：CD 39 Tr 1在Tr 1细胞稳定性和功能中的作用是什么？ CD 39 Tr 1缺陷损害Tr 1细胞中AHR驱动的基因表达和抑制功能。这些数据表明通过消耗eATP，CD 39 Tr 1稳定了Tr 1细胞的AHR驱动的转录程序。因此，在本发明中，本研究拟：1）明确CD 39 Tr 1在实验性自身免疫性T细胞中对Tr 1细胞稳定性的作用脑脊髓炎（EAE）。2)确定eATP和缺氧对Tr 1细胞稳定性的影响及其控制， CD39Tr1。3)建立eATP和缺氧对Tr 1细胞转录程序的影响。具体目标2：CD 39 Tr 1是否控制人Tr 1细胞？ AHR/CD 39和eATP/HIF 1 α对人Tr 1细胞的作用及其治疗潜力尚不清楚。因此，我们提出：1）建立AHR/CD 39和eATP-缺氧/HIF 1 α在人肝癌细胞分化中的作用，人Tr 1细胞。2)确定CD 39 + Tr 1细胞缺陷是否与MS相关。具体目标3：CD 39 DC如何控制Tr 1细胞？ CD 39 DC促进体外T细胞表达IL-10并限制自身免疫性炎症。因此，我们建议目的：1）确定CD 39 DC在体内控制Tr 1细胞中的作用。2)确定eATP信号在T细胞中的作用 CD 39 DC对Tr 1细胞的作用。3)明确CD 39 DC对DC表型和功能的影响。总之，我们在小鼠和人类系统中使用独特的工具来研究控制Tr 1的新途径。细胞，以及MS和其他自身免疫性疾病的潜在治疗靶点。 2

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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