Function of a novel subset of dendritic cells in EAE

EAE 中树突状细胞的新亚群的功能

• 批准号: 8386516
• 负责人: Estelle Bettelli
• 金额: $ 21.6万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386516
• 关键词: Address; Animal Model; Antigen-Presenting Cells; Autoimmune Responses; Autoimmunity; CD4 Positive T Lymphocytes; Cells; Characteristics; Clinical; Demyelinations; Dendritic Cells; Development; Disease; Experimental Autoimmune Encephalomyelitis; Flow Cytometry; Functional disorder; Generations; Growth; Histocompatibility; Histology; ITGAX gene; Immune response; Immune system; Inflammation; Interferon Type II; Interleukin-12; Interleukin-6; Lymphoid; Multiple Sclerosis; Mus; Neuraxis; Organ; Orphan; Pathogenicity; Peripheral; Play; Population; RNA; Regulation; Reporter; Retinoids; Role; STAT1 gene; STAT4 gene; T cell response; T-Lymphocyte; T-bet protein; Testing; Th1 Cells; innovation; insight; interleukin-23; new therapeutic target; novel; prevent; receptor; transcription factor

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) characterized by inflammation and demyelination of the CNS. Two subsets of CD4+ T cells, Th1 and Th17 cells, have been implicated in the pathogenicity of MS and EAE. The interactions between CD4+ T cells and major histocompatibility class II (MHCII)+ antigen presenting cells (APCs) are necessary in both the periphery and central nervous system (CNS) to elicit autoimmunity. Clinical manifestations of EAE do not only require the initial priming of naive autoreactive CD4+ T cells in the peripheral immune system but critically depends on the reactivation of neuroantigen-specific CD4+ T cells within the CNS to develop into effector T cells. Dendritic cells are a heterogeneous class of professional antigen-presenting cells (APCs) capable of initiating, amplifying and regulating immune responses. During ongoing EAE and MS, a substantial accumulation of dendritic cells (DC) has been found in the CNS supporting their active participation in the pathophysiology of the diseases. Conventional DCs have been implicated in priming and the amplification of the pathogenic T cell response in EAE. On the other hand, another subset of dendritic cells, plasmatoid DC have been shown to have regulatory roles in the disease. Understanding the function and regulation of different subsets of dendritic cells is therefore important because these cells could serve as a means to regulate or exacerbate autoimmune responses in EAE and MS. Using a reporter mouse, which tracks retinoid-related orphan receptor-gt (RORgt)- expressing cells, we discovered a new population of dendritic cells characterized by the expression of RORgt, the transcription factor important for the development of Th17 cells. We did not detect these cells in the lymphoid organs or CNS of naive mice. However, we observed these new CD11c+ RORgt+ dendritic cells in the CNS of mice with active EAE. In this proposal, we will test the innovative hypothesis that this subset of RORgt+ CD11c+ dendritic cells (DCs) represents a unique subset of dendritic cells and is important for the development of EAE and the restimulation of pathogenic Th17 cells in the CNS. We will (1) characterize these RORgt + dendritic cells by flow cytometry, histology and RNA-seq, and (2) determine the function of RORgt+ DCs in EAE. The completion of these studies will provide novel insights on the role of a newly identified subset of dendritic cells that expresses RORgt in the induction and modulation of pathogenic T cell responses. Addressing these questions will significantly contribute to our understanding of the ontogeny of dendritic cells an important cell subset of the immune system and hopefully identify new strategies aimed at preventing the activation and entry of pathogenic cell in the CNS during autoimmunity. PUBLIC HEALTH RELEVANCE: Dendritic cells play an important role in the generation, amplification, and regulation of the autoimmune response in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). The purpose of this project is to determine the characteristics of a novel subset of dendritic cells and determine their function in the development of EAE.

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是一种以中枢神经系统炎症和脱髓鞘为特征的多发性硬化症（MS）动物模型。CD4+ T细胞的两个亚群Th1和Th17细胞与MS和EAE的致病性有关。CD4+ T细胞与主要组织相容性II类(MHCII)+抗原呈递细胞（APCs）之间的相互作用在外周和中枢神经系统（CNS）中都是引发自身免疫的必要条件。EAE的临床表现不仅需要初始启动外周免疫系统的初始自身反应性CD4+ T细胞，而且严重依赖于中枢神经系统内神经抗原特异性CD4+ T细胞的再激活，以发展为效应T细胞。树突状细胞是一类异质性的专业抗原呈递细胞（APCs），能够启动、放大和调节免疫反应。在持续的EAE和MS过程中，在中枢神经系统中发现大量树突状细胞（DC）的积累，支持它们积极参与疾病的病理生理。常规dc与EAE致病性T细胞反应的启动和扩增有关。另一方面，树突状细胞的另一个子集，浆样DC已被证明在疾病中具有调节作用。因此，了解树突状细胞不同亚群的功能和调控是很重要的，因为这些细胞可以作为调节或加剧EAE和ms的自身免疫反应的手段。使用一个追踪类视黄酮相关孤儿受体-gt （RORgt）表达细胞的报告小鼠，我们发现了一个以RORgt表达为特征的新树突状细胞群，RORgt是Th17细胞发育的重要转录因子。我们未在幼稚小鼠的淋巴器官或中枢神经系统中检测到这些细胞。然而，我们在EAE活性小鼠的中枢神经系统中观察到这些新的CD11c+ RORgt+树突状细胞。在本研究中，我们将验证这一创新假设，即RORgt+ CD11c+树突状细胞（dc）的这一子集代表了树突状细胞的一个独特子集，对EAE的发展和CNS中致病性Th17细胞的再刺激很重要。我们将(1)通过流式细胞术、组织学和RNA-seq对这些RORgt+树突状细胞进行表征；(2)确定RORgt+树突状细胞在EAE中的功能。这些研究的完成将为新发现的表达RORgt的树突状细胞亚群在诱导和调节致病性T细胞反应中的作用提供新的见解。解决这些问题将大大有助于我们对免疫系统重要细胞亚群树突状细胞的个体发生的理解，并有希望确定新的策略，旨在防止自身免疫过程中致病性细胞进入中枢神经系统的激活和进入。