MOG-Specific T Cell Trafficking in the Central Nervous System

项目概述多发性硬化症（MS）是一种中枢神经系统的神经炎症性疾病。MS患者临床表现多样，反映了脑和脊髓白质径道炎症浸润、脱髓鞘斑块和轴突损伤的广泛分布。实验性过敏性脑脊髓炎（EAE）是通过刺激T细胞介导的髓鞘抗原免疫诱导MS的动物模型。EAE与MS有许多相似之处，包括白质中存在炎症浸润和脱髓鞘。然而，与多发性硬化症不同的是，病变主要局限于脊髓，在大脑中可见的炎症明显较少。因此，大多数啮齿动物EAE模型不适合研究针对大脑和脊髓炎症的机制。我们开发了一种独特的EAE模型，使我们能够确定中枢神经系统中不同炎症模式的基础。C3HeB/Fej x C3H。SW F1小鼠产生的T细胞特异性为髓鞘少突胶质细胞糖蛋白（MOG）的三个表位：MOG97-114、MOG79-90和MOG35-55。过继性转移mog97 -114特异性T细胞诱导的炎症主要发生在脑部而非脊髓，而MOG79-90和mog35 -55特异性T细胞诱导的炎症主要发生在脊髓而非脑部。对所有三个表位特异性的T细胞产生IL-17+和IFN-3+细胞，然而，对于mog97 -114特异性的T细胞，IL-17:IFN-3比例显着更高。通过控制每种特异性的Th17:Th1比率，我们证明炎症细胞在脑与脊髓中的定位是由髓鞘特异性Th17和Th1细胞的比率调节的，而不是由髓鞘特异性Th17和Th1细胞的绝对数量或表位特异性。有趣的是，与MOG79-90或mog35 -55特异性T细胞相比，MOG97-114特异性T细胞对其抗原也表现出更高的功能亲和力。我们建议验证以下假设：1)T细胞对抗原的功能亲和力决定了应答群体中Th17:Th1的比例；2)Th17和Th1细胞在迁移、存活和/或在大脑中与脊髓中增殖的能力不同；3)脑和脊髓内的常驻细胞对偏向Th17或Th1的浸润T细胞群体的反应不同。在多发性硬化症中，炎性病变通常播散在脑白质中，并经常播散在脊髓中；然而，在大多数啮齿类动物多发性硬化症模型中，病变主要发生在脊髓，几乎没有脑炎症。我们开发了一种独特的小鼠模型，其中由不同类型的致病性T细胞介导的机制将被定义为调节脑与脊髓炎症。更好地了解不同的T细胞亚群如何、在哪里以及为什么在中枢神经系统中启动和维持炎症，对于预测在MS治疗中操纵这些T细胞活性的疗效和后果至关重要。

DESCRIPTION (provided by applicant): Project Summary Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system. The diverse clinical signs seen in MS patients reflect the wide distribution of inflammatory infiltrates, demyelinating plaques and axonal damage in the white matter tracks of the brain and spinal cord. Experimental allergic encephalomyelitis (EAE) is an animal model of MS that is induced by stimulating T cell-mediated immunity to myelin antigens. EAE has many similarities to MS, including the presence of inflammatory infiltrates and demyelination in the white matter. Unlike MS, however, the lesions are restricted predominantly to the spinal cord with significantly less inflammation seen in the brain. Thus, most rodent EAE models are not amenable to investigate mechanisms for targeting inflammation to the brain as well as the spinal cord. We have developed a unique model of EAE that allows us to determine the basis for different patterns of inflammation in the CNS. C3HeB/Fej x C3H.SW F1 mice generate T cells specific for three epitopes of myelin oligodendrocyte glycoprotein (MOG): MOG97-114, MOG79-90 and MOG35-55. Adoptive transfer of MOG97-114-specific T cells induces inflammation predominantly in the brain and not the spinal cord, while transfer of MOG79-90 and MOG35-55-specific T cells induces inflammation localized in the spinal cord and not the brain. T cells specific for all three epitopes generate IL-17+ and IFN-3+ cells, however, the IL-17:IFN-3 ratio is significantly higher for MOG97-114-specific T cells. By manipulating Th17:Th1 ratios for each specificity, we demonstrate that the localization of inflammatory cells in the brain versus the spinal cord is regulated by the ratio, and not the absolute number or epitope specificity, of myelin-specific Th17 and Th1 cells. Interestingly, MOG97-114 specific T cells also exhibit a higher functional avidity for their antigen compared to either MOG79-90 or MOG35-55-specific T cells. We propose to test the hypotheses that 1) T cell functional avidity for antigen determines the Th17:Th1 ratio in the responding population, 2) Th17 and Th1 cells differ in their ability to either migrate to, survive in, and/or proliferate in the brain versus the spinal cord and 3) resident cells within the brain and spinal cord differ in their response to infiltrating T cell populations biased toward Th17 or Th1.Project Narrative In multiple sclerosis, inflammatory lesions are typically disseminated in the white matter of the brain and frequently the spinal cord; however, lesions in most rodent models of MS predominate in the spinal cord with little brain inflammation. We developed a unique mouse model in which mechanisms mediated by different types of pathogenic T cells will be defined that regulates brain versus spinal cord inflammation. A better understanding of how, where and why different T cell subsets initiate and sustain inflammation in the central nervous system is critical to predict the efficacy and consequences of manipulating the activity of these T cells in MS therapies.