CNS-Specific Regulatory CD8+ T Cells in Autoimmune Demyelination

描述（由申请人提供）：多发性硬化（MS）是一种中枢神经系统（CNS）的炎性脱髓鞘疾病。我们对MS的免疫过程的大量理解来自于对其自身免疫动物模型，实验性自身免疫性脑脊髓炎（EAE）的研究。然而，绝大多数EAE和MS的研究都集中在评估和靶向CD 4 + T细胞应答，一般假设这些疾病主要是Th 1/Th 17介导和Th 2/Treg调节的。近年来的研究表明，CD 8 + T细胞在自身免疫性脱髓鞘的发病机制和调节中可能起重要作用。CD 8 + T细胞在自身免疫病理学过程中的作用一直是研究不足和有争议的。虽然已知CD 8 + 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。MS患者以及多种EAE模型中CNS特异性CD 8 + T细胞的患病率很高。虽然它使直观的意义，CNS靶向的，MHC I类限制性CD 8 + T细胞反应可能在疾病中具有致病作用，我们最近的研究已经产生了第一个证据，神经抗原特异性CD 8 + T细胞在EAE中的一种新的和意想不到的免疫抑制作用。因此，我们假设CNS特异性CD 8 + T细胞在自身免疫性脱髓鞘疾病期间形成内在免疫调节的重要手臂。我们建议，可以利用这一自然过程来制定有效的免疫策略。本申请中提出的实验将直接解决CNS反应性CD 8 + T细胞的免疫调节机制，描述其细胞、分子和运输要求。此外，将定义该群体中最有效的免疫抑制子集，目的是开发新的免疫抑制方法。我们相信，拟议的实验将为健康和疾病期间CD 8 + T细胞介导的免疫调节提供更深入的基本见解，并将为这种和其他免疫介导的疾病的新干预策略铺平道路。 公共卫生相关性：实验性自身免疫性脑脊髓炎（EAE）是人类免疫介导疾病多发性硬化症（MS）的小鼠模型。我们已经发现了中枢神经系统靶向的CD 8+免疫细胞在这种疾病的背景下的新的免疫抑制作用。在拟议的研究中，我们将剖析这种抑制的机制，目的是为这种疾病制定创新的治疗策略，并为MS免疫学的一个被忽视的领域提供重要的见解。

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.