MOG-Specific T Cell Trafficking in the Central Nervous System

描述(申请人提供)：项目摘要多发性硬化症(MS)是一种中枢神经系统炎症性疾病。MS患者的不同临床体征反映了脑白质和脊髓白质轨迹中广泛分布的炎性浸润物、脱髓鞘斑块和轴突损伤。实验性变态反应性脑脊髓炎(EAE)是一种通过刺激T细胞介导的对髓鞘抗原的免疫而诱导的多发性硬化的动物模型。EAE与MS有许多相似之处，包括白质中存在炎性浸润物和脱髓鞘。然而，与多发性硬化症不同的是，病变主要局限于脊髓，大脑中的炎症明显较少。因此，大多数啮齿动物EAE模型不能研究炎症靶向大脑和脊髓的机制。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不同炎症模式的基础。C3HeB/Fej x C3H.SW F1小鼠产生针对髓鞘少突胶质细胞糖蛋白(MOG)三个表位的T细胞：MOG97-114、MOG79-90和MOG35-55。过继转移MOG97-114特异性T细胞主要在脑而不是脊髓引起炎症，而转移MOG79-90和MOG35-55特异性T细胞则诱导局部炎症在脊髓而不是脑。三种表位的特异性T细胞均可产生IL-17+和干扰素-3+细胞，但MOG97-114特异性T细胞的IL-17/干扰素-3比率显著高于MOG97-114。通过操纵每种特异性的Th17：Th1比率，我们证明了炎症细胞在大脑和脊髓中的定位是由髓鞘特异性Th17和Th1细胞的比率而不是绝对数量或表位特异性来调节的。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。我们建议测试的假设是：1)T细胞对抗原的功能亲和力决定了应答人群中的Th17：Th1比率，2)Th17和Th1细胞在迁移到脑内、在脑内存活和/或在脑内增殖的能力不同于脊髓，3)脑和脊髓内的驻留细胞对倾向于Th17或Th1的浸润性T细胞群的反应不同。项目叙述在多发性硬化症中，炎性病变通常扩散到脑白质，经常是脊髓；然而，大多数MS啮齿动物模型中的病变主要分布在脊髓，几乎没有脑炎症。我们开发了一种独特的小鼠模型，在该模型中，将确定不同类型的致病T细胞介导的机制，以调节大脑对脊髓的炎症。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启动和维持炎症，对于预测在MS治疗中操纵这些T细胞的活性的效果和后果至关重要。

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.