Transcriptional Control of Autoimmunity in the Central Nervous System

描述(由申请人提供)：这是一份修改后的PPG申请，目的是更好地了解T细胞在自身免疫中的机制，这源于T效应细胞和T调节细胞的关键调节因子的发现。我们发现IL-27和转录因子芳香烃受体(AhR)在动物和人类的免疫反应中起着核心作用，这些途径影响到获得性和先天免疫功能的各个方面，包括Tregs、Th17细胞和树突状细胞。人们对这些新途径知之甚少，它们似乎在中枢神经系统炎症中至关重要，并与多发性硬化症等疾病直接相关。 该计划项目拨款(PPG)的主要目标是确定IL-27如何抑制效应T细胞和诱导调节性TR1细胞的分子机制，重点是两个转录因子cMaf和AhR，这两个转录因子都是由IL-27在应答TR1细胞中诱导的。在动物模型和MS患者中研究细胞因子和转录因子的相互关系将有助于更好地了解MS的免疫异常，并有助于开发更具特异性的免疫调节疗法，并从机制上了解目前用于治疗MS的治疗方法。干扰素是MS中广泛使用的一线疗法，已被证明部分通过诱导IL-27发挥作用，强调了研究这一途径在中枢神经系统自身免疫中的重要性。 PPG汇集了四名研究人员，每一人都具有独特的优势和专业知识来调查这一新领域。项目1：(Kuchroo)《EAE中效应和调节性T细胞的转录调控》(Littman)《TR1细胞的转录网络分析》(Quintana)项目3：《AhR在EAE发展过程中控制先天免疫反应的作用》和项目4(Weiner)《IL-27和AhR在调节健康受试者和MS患者人体效应和调节性T细胞中的作用》。 修订后的PPG将建立一个由两部分组成的多层次表达分析核心：项目2将使用RNA-seq和ChlP-seq技术进行表达分析，核心B将使用最新的数字纳米串技术进行多重表达分析，以分析亚组和稀有种群中转录本的表达。核心将为所有项目提供服务。一个行政核心将协调PPG的各个行政方面，并已组建了一个科学咨询委员会，以提供科学监督。

DESCRIPTION (provided by applicant): This is a revised PPG application to build a better understanding of T cell mechanisms in autoimmunity that has stemmed from the discovery of critical regulators of both T effector and T regulatory cells. We have discovered that IL-27 and the transcription factor aryl hydrocarbon receptor (AhR) play central roles in immune responses in animals and humans and these pathways impinge on all aspects of immune function, both adaptive and innate and include Tregs, Th17 cells and dendritic cells. Little is known about these new pathways, which appear crucial in CNS inflammation and have direct relevance to diseases such as multiple sclerosis. The primary goal of this program project grant (PPG) is to identify molecular mechanisms of how IL-27 inhibits effector T cells and induces regulatory Tr1 cells with a focus on two transcription factors cMaf and AhR, both of which are induced by IL-27 in responding Tr1 cells. The investigation of the inter-relationship of cytokines and transcription factors in both animal models and MS patients will allow a better basic understanding of immune abnormalities in MS and allow both the development of more specific immunomodulatory therapy and a mechanistic understanding of current therapies being used to treat MS. IFN¿, a widely used first line therapy in MS has been shown to act in part by the induction of IL-27, underscoring the importance of studying this pathway in CNS autoimmunity. This PPG brings together four investigators, each with unique strengths and expertise to investigate this new area. Project 1: (Kuchroo) "Transcriptional regulation of effector and regulatory T cells in EAE; Project 2: (Littman) "Transcriptional network analysis of Tr1 cells." Project 3: (Quintana) "Role of AhR in the control of the innate immune response during the development of EAE." and Project 4: (Weiner) "Role of IL-27 and AhR in the regulation of human effector and regulatory T cells in healthy subjects and MS patients." The revised PPG will establish a Multi-tiered Expression Analysis Core consisting of two components: Project 2 will undertake expression analysis using RNA-seq and ChlP-seq technologies and Core B will undertake multiplex expression analysis using the latest digital Nanostring technology to analyze the expression of transcripts in subsets and rare populations. The core will service all projects. An Administrative Core will coordinate the various administrative aspects of the PPG and a Scientific Advisory Board has been assembled to provide scientific oversight.