Mechanisms by which CD8 T cells shape CNS autoimmunity initiated by CD4 T cells

描述(申请人提供)：多发性硬化症(MS)是一种毁灭性的中枢神经系统(CNS)脱髓鞘疾病，是导致年轻人神经功能障碍的主要原因。自身反应性髓鞘特异性T细胞被认为是多发性硬化症的始作俑者，并在整个疾病过程中起着重要的致病作用。开发MS的治疗方法一直是具有挑战性的，部分原因是在炎症浸润物、病变和临床过程中看到的异质性表明，特定致病机制的相对贡献可能在不同的患者中有所不同。这种异质性可能反映了招募到中枢神经系统的诱导组织的效应细胞类型的个体差异。 通过不同的机制造成损害。由于组织内的炎症环境是动态的，将反映具有不同活动的特定T细胞亚群的相对丰度，这一事实产生了额外的复杂性。因此，更好地了解同一微环境中不同T细胞亚群的激活如何相互影响，以及它们与中枢神经系统驻留细胞的相互作用如何共同作用以传播炎症和诱导组织损伤，对于开发有效的治疗干预措施是至关重要的。在多发性硬化症和实验性自身免疫性脑脊髓炎(EAE)的动物模型中，已经广泛研究了CD4+髓鞘特异性T细胞的作用。产生干扰素的Th1细胞和产生IL-17的Th17细胞两个CD4+效应T细胞亚群参与了MS的发病过程，这些亚群在EAE的中枢神经系统(CNS)内诱导了不同的炎症模式。CD8+髓鞘特异性T细胞的作用尚未得到很好的研究，尽管大量数据表明CD8+T细胞在MS中的作用，但几乎没有建立模型来研究CD8+T细胞在MS中的作用，因此，对于这个T细胞亚群如何影响疾病过程知之甚少。这项申请建议使用新开发的工具来研究CD8+髓鞘特异性T细胞影响由CD4+T细胞发起的EAE的机制。我们的基本假设是，在由CD4+T细胞发起的疾病过程中，髓鞘特异的CD8+T细胞被招募到中枢神经系统，同时但不同的CD4+和CD8+T细胞的活动决定了病变形成、组织损伤和临床体征的模式。我们提出了三个目标来验证这一假说：1.确定髓鞘特异性CD8+T细胞的募集如何改变由CD4+T细胞诱导的急、慢性EAE的病程。2：确定CD8+T细胞在CD4T细胞发起的EAE期间被招募到中枢神经系统所获得的效应功能。3.检测髓鞘特异性CD8+T细胞对TH1和TH17细胞诱导的CNS自身免疫的影响。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a devastating, demyelinating disease of the central nervous system (CNS) and is the leading cause of neurological disability in young adults. Self-reactive myelin-specific T cells are believed to initiate MS and to play a prominent pathogenic role throughout the course of disease. Developing therapies for MS has been challenging, in part because the heterogeneity seen in inflammatory infiltrates, lesions and clinical course suggest that the relative contribution of specific pathogenic mechanisms may vary among individual patients. This heterogeneity may reflect individual variation in the types of effector cells recruited to the CNS that induce tissue damage via distinct mechanisms. An additional level of complexity arises from the fact that the inflammatory milieu within the tissue is dynamic and will reflect the relative abundance of specific T cells subsets with different activities. Thus, a better understanding of how the activit of distinct T cell subsets in the same microenvironment influence each other and how their interactions with CNS resident cells act in concert to promulgate inflammation and induce tissue damage, is essential to develop effective therapeutic intervention. The role of CD4+ myelin-specific T cells has been extensively studied in MS and the animal model experimental autoimmune encephalomyelitis (EAE). Two CD4+ effector T cell subsets, IFN-?- producing Th1 cells and IL-17-producing Th17 cells, have been implicated in the pathogenesis of MS, and these subsets induce different inflammatory patterns within the central nervous system (CNS) in EAE. The role of CD8+ myelin-specific T cells has not been well-studied, even though a large body of data implicates a role for CD8+ T cells in MS. Few models have been developed to study the role of CD8+ T cells in MS, therefore little is known about how this T cell subset influences the disease process. This application proposes to use newly developed tools to investigate the mechanisms by which CD8+ myelin-specific T cells influence EAE initiated by CD4+ T cells. Our fundamental hypothesis is that myelin-specific CD8+ T cells are recruited to the CNS during disease initiated by CD4+ T cells, and that the simultaneous, but distinct, activities of CD4+ and CD8+ T cells determine the pattern of lesion formation, tissue damage and clinical signs. Three aims are proposed to test this hypothesis: 1. DETERMINE HOW RECRUITMENT OF MYELIN-SPECIFIC CD8+ T CELLS MODIFIES THE COURSE OF ACUTE AND CHRONIC EAE INDUCED BY CD4+ T CELLS. 2: DEFINE THE EFFECTOR FUNCTIONS ACQUIRED BY CD8+ T CELLS RECRUITED TO THE CNS DURING CD4 T CELL-INITIATED EAE. 3: DETERMINE THE INFLUENCE OF MYELIN-SPECIFIC CD8+ T CELLS ON CNS AUTOIMMUNITY INDUCED BY TH1 VERSUS TH17 CELLS.