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Function of a novel subset of dendritic cells in EAE

EAE 中树突状细胞的新亚群的功能

基本信息

批准号：
8469105
负责人：
Estelle Bettelli
金额：
$ 25.01万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

项目摘要

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.

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CNS炎症和脱髓鞘为特征的多发性硬化（MS）动物模型。两个亚群的CD 4 + T细胞，Th 1和Th 17细胞，已牵连在MS和EAE的致病性。在外周和中枢神经系统（CNS）中，CD 4 + T细胞和主要组织相容性II类（MHCII）+抗原呈递细胞（APC）之间的相互作用是引发自身免疫所必需的。EAE的临床表现不仅需要外周免疫系统中初始自身反应性CD 4 + T细胞的初始引发，而且关键地依赖于CNS内神经抗原特异性CD 4 + T细胞的再活化以发育成效应T细胞。树突状细胞是一类异质性的专职抗原呈递细胞（APC），能够启动，放大和调节免疫反应。在进行中的EAE和MS，大量的树突状细胞（DC）的积累已被发现在中枢神经系统支持他们积极参与疾病的病理生理。传统的DCs与EAE中致病性T细胞应答的引发和扩增有关。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，了解树突状细胞的不同亚群的功能和调节是重要的，因为这些细胞可以作为调节或加剧EAE和MS中自身免疫应答的手段。使用追踪类维生素A相关孤儿受体-gt（RORgt）表达细胞的报告小鼠，我们发现了一种新的树突状细胞群体，其特征在于RORgt的表达，该转录因子对Th 17细胞的发育很重要。我们没有检测到这些细胞在幼稚小鼠的淋巴器官或中枢神经系统。然而，我们在患有活动性EAE的小鼠的CNS中观察到这些新的CD 11 c + RORgt+树突状细胞。在这项提案中，我们将测试的创新假设，RORgt+ CD 11 c+树突状细胞（DC）的这一子集代表了一个独特的树突状细胞的子集，是重要的EAE的发展和再刺激的致病性Th 17细胞在中枢神经系统。我们将（1）通过流式细胞术、组织学和RNA-seq表征这些RORgt +树突状细胞，和（2）确定RORgt+ DC在EAE中的功能。这些研究的完成将提供新的见解的作用，一个新发现的树突状细胞亚群，表达RORgt的诱导和调节致病性T细胞反应。这些问题的解决将大大有助于我们了解树突状细胞的个体发育的免疫系统的一个重要的细胞亚群，并有希望找到新的策略，旨在防止激活和进入中枢神经系统的病原细胞在自身免疫。