CD8+ T cells Control Autoimmunity in EAE

CD8 T 细胞控制 EAE 中的自身免疫

• 批准号: 7148445
• 负责人: HONG JIANG
• 金额: $ 40.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148445
• 关键词: autoimmunity; peptides

DESCRIPTION (provided by applicant): We have previously demonstrated that Qa-1 dependent CD8+ T cells control the peripheral self-reactive TCR repertoire in EAE mice by selectively down-regulating some but not all MBP reactive T cell clones which have higher growth potential to MBP and enriched in the potentially pathogenic MBP-reactive clones. In recent studies we further demonstrated that Qa-1 dependent CD8+ T cells are biologically involved in the development and maintenance of peripheral tolerance to the self-antigen HEL in HEL transgenic mice. We provide experimental evidence that the strategy employed by the Qa-1 dependent CD8+ T cells to accomplish these tasks in vivo is to selectively down-regulate CD4+ T cell clones that are of intermediate, but not high or low, affinity/avidity responding to HEL. In this application we will extend our studies to the EAE model to further identify the cellular and molecular mechanisms that define the specific interaction between the Qa-1 dependent CD8+ T cells and the self-reactive CD4+ T cells. We will identify the peripheral self- reactive repertoire and the relationship between affinity/avidity and pathogenicity of self-reactive T cells in EAE model to further understand how preferential down regulation of certain affinity/avidity clones by the Qa- 1 dependent CD8+ T cells provides a mechanism to control the pathogenic auto-immunity in the periphery. We will also identify and test Qa-1 binding peptide/s which render the activated T cells susceptible to the down-regulation by the CD8+ T cell thus protect the animals from auto-immune disease. In addition, we will characterize the immune functions of the Qa-1 dependent CD8+ T cells in EAE by identifying the TCR Va and Vp repertoire of the CD8+ T cells and defining the other immunologic functions mediated by CD8+ T cells. In this regard, unlike HEL transgenic mice model system, EAE model is a classical autoimmune disease model which has its unique advantage that HEL transgenic mice model system does not have. Particularly, the major classical auto-immune disease models currently used, such as NOD mice, NZB/NZW mice and B10PL/EAE mice are all Qa-1 a hyplotype. Qa-1 is one of the crucial components of this regulatory pathway, which may lead to the therapeutic application in preventing and treating auto-immune disease. So that it is very important to test the biological function of Qa-1 in Qa-1 strains such as B10PL mice in auto- immune disease models. Future application of this regulatory pathway in man is based on evidence that the human homologue of Qa-1, HLA-E, can function as a restricting element for human regulatory CD8+ T cells. Thus, the studies will provide theoretical basis for clinical application of this regulatory pathway in prevention and treatment of multiple sclerosis in man.

描述（由申请人提供）：我们先前已经证明，通过选择性地调节一些MBP反应性T细胞克隆，具有较高的MBP生长潜力，并在潜在的病态的MBP-MBP激发中富含MBP的生长潜力，从而控制了EAE小鼠中的QA-1依赖性CD8+ T细胞在EAE小鼠中控制周围的自我反应性TCR曲目。在最近的研究中，我们进一步证明，QA-1依赖性CD8+ T细胞在生物学上参与了对HEL转基因小鼠中自抗原HEL的外周耐受性的发展和维持。我们提供了实验证据，表明QA-1依赖的CD8+ T细胞在体内完成这些任务的策略是选择性地下调中间体但不高的CD4+ T细胞克隆，但不是高或低的亲和力/患者对HEL的反应。在此应用中，我们将将研究扩展到EAE模型，以进一步确定定义QA-1依赖性CD8+ T细胞与自我反应性CD4+ T细胞之间特定相互作用的细胞和分子机制。我们将确定EAE模型中自我反应性T细胞亲和力/亲和力和致病性之间的关系的外围性自我反应性曲目，以进一步了解如何优先降低QA-1依赖性CD8+ T细胞对某些亲和力/亲和力克隆的优先调节，从而提供了一种机制，可以提供一种控制外围病原体中的致病性自身免疫性的机制。我们还将识别和测试QA-1结合肽/S，从而使活化的T细胞易受CD8+ T细胞下调的影响，从而保护动物免受自身免疫性疾病的侵害。此外，我们将通过识别CD8+ T细胞的TCR VA和VP库并定义由CD8+ T细胞介导的其他免疫学函数，来表征EAE中QA-1依赖CD8+ T细胞的免疫功能。在这方面，与HEL转基因小鼠模型系统不同，EAE模型是一种经典的自身免疫性疾病模型，其独特的优势是HEL转基因小鼠模型系统没有。特别是，当前使用的主要经典自身免疫性疾病模型，例如NOD小鼠，NZB/NZW小鼠和B10PL/EAE小鼠都是质量质量质量标准的。 QA-1是该调节途径的关键组成部分之一，这可能导致预防和治疗自身免疫性疾病的治疗应用。因此，在自动免疫疾病模型中测试QA-1菌株（例如B10PL小鼠）的生物学功能非常重要。这种调节途径在人类中的未来应用是基于证据表明，QA-1 HLA-E的人类同源物可以作为人类调节性CD8+ T细胞的限制元素。因此，该研究将为这种调节途径在预防和治疗人的多发性硬化症中的临床应用提供理论基础。