Mechanisms of CD4+CD25+ T Regulatory Cells in EAE

描述（申请人提供）：多发性硬化症（MS）是一种免疫介导的中枢神经系统（CNS）疾病，其特征是血管周围CD4 + T细胞和单个核细胞浸润，随后轴突轨道原发性脱髓鞘导致进行性瘫痪。MS通常被认为是一种自身免疫性疾病，涉及自身反应性T细胞对MBP、PLP和/或髓磷脂少突胶质细胞糖蛋白（MOG）的反应，但髓磷脂反应性与疾病病理之间的明确因果关系尚未得到证实。虽然MS通常被认为与自身免疫性病理有关，但其病因知之甚少，并且用于特异性抑制和预防持续疾病的治疗策略有限。我们建议研究影响MS易感性和进展的内在调节机制，使用两种实验性自身免疫性脑脊髓炎（EAE）小鼠模型，它们要么遵循复发缓解（R-EAE），要么遵循慢性（C-EAE）病程。CD4+CD25 +调节性T细胞（TR）是CD4+ T细胞反应的有效抑制剂，CD4+ T细胞反应通过抗原特异性方式通过TCR交联激活，并已被证明对几种自发自身免疫性疾病（如糖尿病和自身免疫性胃炎）的启动具有介导保护作用。我们的初步数据清楚地表明，补充TR通过抑制初始和先前激活的脑源性CD4 + T细胞的增殖和效应功能，显著防止EAE的启动，而这些细胞的消耗或失活导致疾病症状加剧。我们还表明，tr介导的疾病抑制与髓磷脂肽特异性保护性Th2细胞外周淋巴器官频率增加和浸润中枢神经系统的单核细胞数量显著减少有关。本实验将验证CD4+CD25 + TR在EAE易感性抵抗和通过诱导对疾病相关的自髓磷脂肽的抗原特异性无反应调节疾病进展中发挥关键作用的假设。本实验将阐明TR在急性和复发性EAE中抑制致脑效应Thl细胞功能活性的细胞和分子机制，从而阻断临床脱髓鞘疾病的发生/进展。AIM 1将确定CD4+CD25 + TR在调节R-EAE和C-EAE的起始、进展和恢复阶段中的作用。AIM 2将确定CD4+CD25 + TR对年龄、性别和菌株相关的EAE易感性的贡献。AIM 3将阐明CD4+CD25 + TR影响脑源性T细胞激活、扩增、运输和/或效应功能的机制。这些研究将进一步加深我们对TR在调节中枢神经系统自身免疫的诱导和进展中的作用的理解，并为优化旨在增强人类自身免疫性疾病预防和治疗的内在调节机制的策略提供重要信息。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) disease characterized by perivascular CD4 + T cell and mononuclear cell infiltration with subsequent primary demyelination of axonal tracks leading to progressive paralysis. MS is generally considered to be an autoimmune disease involving autoreactive T cell responses to MBP, PLP, and/or myelin-oligodendrocyte glycoprotein (MOG), however a clear cut cause-effect relationship between myelin reactivity and disease pathology has yet to be demonstrated. Although MS is generally considered to involve an autoimmune pathology, little is known regarding its etiology and there are limited therapeutic strategies available to specifically inhibit and prevent ongoing disease. We propose to investigate intrinsic regulatory mechanisms that influence both the susceptibility to and progression of MS using two mouse models of experimental autoimmune encephalomyelitis (EAE) that either follow a relapsingremitting (R-EAE) or chronic (C-EAE) disease course. CD4+CD25 + regulatory T cells (TR) are potent inhibitors of CD4 + T cell responses that are activated in an antigen-specific manner via TCR cross-linking and have been shown to mediate protection against the initiation of several spontaneous autoimmune disorders, such as diabetes and autoimmune gastritis. Our preliminary data clearly demonstrate that supplementation of TR significantly protects against the initiation of EAE by inhibiting the proliferation and effector function of both naive and previously-activated encephalitogenic CD4 + T cells, while depletion or inactivation of these cells leads to exacerbated disease symptoms. We have also shown that TR-mediated disease inhibition is associated with an increased frequency of myelin peptide-specific protective Th2 cells within the peripheral lymphoid organs and significantly decreased numbers of mononuclear cells infiltrating the CNS. The experiments in this proposal will test the hypothesis that CD4+CD25 + TR play a critical role in conferring resistance to EAE susceptibility and in regulating disease progression by inducing antigen-specific unresponsiveness to disease-relevant self-myelin peptides. The proposed experiments will elucidate the cellular and molecular mechanisms by which TR inhibit the functional activity of encephalitogenic effector Thl cells in acute and relapsing EAE, thus blocking the initiation/progression of clinical demyelinating disease. Three specific aims are proposed: AIM 1 will determine the role of CD4+CD25 + TR in modulating the initiation, progression, and recovery phases of R-EAE and C-EAE. AIM 2 will determine the contribution of CD4+CD25 + TR to age-, gender-, and strain-associated susceptibility to EAE. AIM 3 will elucidate the mechanisms by which CD4+CD25 + TR influence encephalitogenic T cell activation, expansion, trafficking, and/or effector function. These studies should further our understanding of the role of TR in regulating both the induction and progression of CNS autoimmunity and provide vital information relative to optimizing strategies designed to enhance intrinsic regulatory mechanisms for the prevention and treatment of human autoimmune diseases.