CNS-SPECIFIC REGULATORY CD8+ T CELLS IN AUTOIMMUNE DEMYELINATION

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的炎症性脱髓鞘疾病。我们对MS背后的免疫过程的理解很大程度上来源于其自身免疫动物模型的研究，实验性自身免疫性脑脊髓炎（EAE）。然而，绝大多数关于EAE和MS的研究都集中在评估和靶向CD4+ T细胞反应上，普遍认为这些疾病主要是由Th1/ th17介导和Th2/ treg调节的。最近来自他人和我们的报道表明，CD8+ T细胞可能在自身免疫性脱髓鞘的发病机制和调节中发挥重要作用。CD8+ T细胞在自身免疫病理过程中的作用一直没有得到充分的研究，也存在争议。虽然已知CD8+ T细胞代表MS病变中的主要T细胞，并且在病理部位寡克隆扩增，但这些细胞的抗原特异性及其作用尚不清楚。多发性硬化症患者以及多种EAE模型中，cns特异性CD8+ T细胞的发生率较高。虽然直观地认为cns靶向，MHC i类限制CD8+ T细胞反应可能在疾病中具有致病性作用，但我们最近的研究首次证明了EAE中神经抗原特异性CD8+ T细胞具有新的和意想不到的免疫抑制作用。因此，我们假设cns特异性CD8+ T细胞在自身免疫性脱髓鞘疾病中形成了一个重要的内在免疫调节臂。我们建议可以利用这种自然过程来开发有效的免疫治疗策略。本应用程序中提出的实验将直接解决cns反应性CD8+ T细胞的免疫调节机制，描述其细胞，分子和运输需求。此外，该人群中最有效的免疫抑制亚群将被定义为开发一种新的免疫治疗方法的目标。我们相信，所提出的实验将为健康和疾病期间CD8+ T细胞介导的免疫调节提供更大的基础见解，并将为这种疾病和其他免疫介导疾病的新干预策略铺平道路。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS). A great deal of our understanding about the immunologic processes that underlie MS derives from studies in its autoimmune animal model, experimental autoimmune encephalomyelitis (EAE). However, the vast majority of studies in EAE and MS have focused on evaluating and targeting CD4+ T cell responses, with the general assumption that these diseases are predominantly Th1/Th17-mediated and Th2/Treg-modulated. Recent reports from others and us indicate that CD8+ T cells may play an important role in the pathogenesis as well as regulation of autoimmune demyelination. The role of CD8+ T cells in the process of autoimmune pathology has been both understudied and controversial. While it is known that CD8+ T cells represent the predominant T cell in an MS lesion and are oligoclonally expanded at the site of pathology, the antigenic specificity of these cells and their role is not known. There is high prevalence of CNS-specific CD8+ T cells in MS patients as well as multiple models of EAE. While it makes intuitive sense that a CNS-targeted, MHC Class I-restricted CD8+ T cell response would likely have a pathogenic role in disease, our recent studies have generated the first evidence for a novel and unexpected immune suppressor role for neuroantigen-specific CD8+ T cells in EAE. We thus hypothesize that CNS-specific CD8+ T cells form an important arm of intrinsic immune regulation during autoimmune demyelinating disease. We propose that this natural process can be harnessed for the development of an effective immunotherapeutic strategy. The experiments proposed in this application will directly address the mechanisms of immune modulation by CNS-reactive CD8+ T cells, delineating their cellular, molecular and trafficking requirements. Moreover, the most potent immune suppressive subset of this population will be defined with the goal of developing a novel immunotherapeutic approach. We believe that the proposed experiments will provide greater fundamental insight into CD8+ T cell-mediated immune regulation during health and disease and will pave the way for newer intervention strategies for this and other immune-mediated diseases. PUBLIC HEALTH RELEVANCE: Experimental autoimmune encephalomyelitis (EAE) is a mouse model for the human immune-mediated disease multiple sclerosis (MS). We have found a novel immune suppressive role for central nervous system- targeted CD8+ immune cells in the context of this disease. In the proposed studies, we will dissect the mechanisms of such suppression with the goal of developing innovative treatment strategies for this disease and providing important insights into an overlooked area of MS immunology.