MOG-Specific T Cell Trafficking in the Central Nervous System

多发性硬化（MS）是一种中枢神经系统的神经炎症性疾病。多发性硬化症患者的临床表现多样，反映了脑和脊髓白色物质轨迹中广泛分布的炎性浸润、脱髓鞘斑块和轴突损伤。实验性变态反应性脑脊髓炎（EAE）是通过刺激T细胞介导的对髓鞘抗原的免疫而诱导的MS的动物模型。EAE与MS有许多相似之处，包括白色物质中存在炎性浸润和脱髓鞘。然而，与MS不同的是，病变主要限于脊髓，在大脑中观察到的炎症明显较少。因此，大多数啮齿动物EAE模型不适合研究将炎症靶向脑以及脊髓的机制。我们已经开发了一种独特的EAE模型，使我们能够确定CNS中不同炎症模式的基础。C3 HeB/Fej x C3H.SW F1小鼠产生对髓鞘少突胶质细胞糖蛋白（MOG）的三个表位特异性的T细胞：MOG 97 -114、MOG 79 -90和MOG 35 -55。MOG 97 -114特异性T细胞的连续转移主要在脑中而不是脊髓中诱导炎症，而MOG 79 -90和MOG 35 -55特异性T细胞的转移诱导位于脊髓中而不是脑中的炎症。对所有三种表位特异性的T细胞产生IL-17+和IFN-3+细胞，然而，IL-17：IFN-3比率对于MOG 97 -114特异性T细胞显著更高。通过操纵每种特异性的Th 17：Th 1比率，我们证明了炎症细胞在脑与脊髓中的定位是由髓鞘特异性Th 17和Th 1细胞的比率而不是绝对数量或表位特异性调节的。有趣的是，与M0 G 79 -90或M0 G 35 -55特异性T细胞相比，M0 G 97 -114特异性T细胞也表现出对其抗原更高的功能性亲合力。我们提出的假设是：1）T细胞对抗原的功能性亲合力决定了应答群体中Th 17：Th 1的比例; 2）Th 17和Th 1细胞在迁移、存活和/或增殖的能力上与脊髓不同; 3）脑和脊髓内的驻留细胞在对倾向于Th 17或Th 1的浸润性T细胞群体的应答上不同。然而，在大多数啮齿类动物的MS模型中，损伤主要在脊髓中，几乎没有脑炎症。我们开发了一种独特的小鼠模型，其中将定义由不同类型的致病性T细胞介导的调节脑与脊髓炎症的机制。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引发和维持炎症对于预测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.