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）是多发性硬化症（MS）的动物模型，其特征是CNS的炎症和脱髓鞘。 CD4+ T细胞Th1和Th17细胞的两个子集与MS和EAE的致病性有关。在周围和中枢神经系统（CNS）中，必须使用CD4+ T细胞与主要组织相容性II类（MHCII）+抗原呈递细胞（APC）之间的相互作用，以引起自身免疫性。 EAE的临床表现不仅需要在周围免疫系统中初始启动幼稚的自身反应性CD4+ T细胞，而且批判性地取决于神经抗原特异性的CD4+ T细胞在o中内源中的神经抗原特异性CD4+ T细胞的重新激活，以发展成效应T细胞。树突状细胞是一种能够启动，扩增和调节免疫反应的专业抗原细胞（APC）的异质类。在正在进行的EAE和MS期间，在中枢神经系统中发现了大量的树突状细胞（DC）积极支持其积极参与疾病的病理生理学。常规DC已与EAE中的致病性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已证明质子层直流在该疾病中具有调节作用。因此，了解树突状细胞不同亚集的功能和调节很重要，因为这些细胞可以用作调节或加剧EAE和MS中自身免疫反应的手段。使用记者小鼠，该小鼠跟踪与类视黄素相关的孤儿受体-GT（RORGT） - 表达细胞，我们发现了一个新的树突状细胞群，其特征在于Rorgt的表达，这对于TH17细胞的发育很重要。我们没有在天真小鼠的淋巴机构或中枢神经系统中检测到这些细胞。但是，我们观察到具有活性EAE小鼠中枢神经系统中的这些新的CD11C+ RORGT+树突状细胞。在此提案中，我们将测试创新的假设，即Rorgt+ CD11C+树突状细胞（DCS）的这一子集代表了树突状细胞的独特子集，并且对于EAE的发展和CNS中的致病性TH17细胞的恢复至关重要。 （1）通过流式细胞仪，组织学和RNA-Seq来表征这些Rorgt +树突状细胞，以及（2）确定Rorgt + DC在EAE中的功能。这些研究的完成将提供有关在致病T细胞反应的诱导和调节中表达RORGT的新鉴定的树突状细胞子集的作用的新见解。解决这些问题将极大地有助于我们理解树突状细胞的个体发育，这是免疫系统的重要细胞子集，并希望确定旨在防止自身免疫期间中枢神经系统中病原细胞激活和进入的新策略。 公共卫生相关性：树突状细胞在实验性自身免疫性脑脊髓炎（EAE）和多发性硬化症（MS）中自身免疫反应的产生，扩增和调节中起重要作用。该项目的目的是确定树突状细胞的新特征，并确定其在EAE发展中的功能。