Regulation by Gammadelta T Cells of Autoimmune Uveitis (EAU)

Gammadelta T 细胞对自身免疫性葡萄膜炎 (EAU) 的调节

• 批准号: 8274129
• 负责人: Deming Sun
• 金额: $ 48.24万
• 依托单位: DOHENY EYE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274129
• 关键词: Adoptive Transfer; Affect; Agonist; Animal Model; Antigens; Autoimmune Diseases; Autoimmune Responses; Biological Assay; Cell physiology; Cells; Complex; Dendritic Cells; Development; Disease; Environmental Risk Factor; Experimental Models; Generations; Goals; Human; Immune; Immune System Diseases; Immune response; Immunization; Immunologics; Immunotherapy; In Vitro; Infection; Inflammatory; Intervention; Knowledge; Laboratories; Modeling; Monitor; Mus; Natural Immunity; Pathway interactions; Play; Population; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research; Role; Shapes; System; T cell regulation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Uses; Time; Uveitis; Vision; Work; adaptive immunity; autoimmune uveitis; autoreactive T cell; base; cytokine; effective therapy; flexibility; improved; in vivo; killer T cell; prevent; response; tool; tumor

DESCRIPTION (provided by applicant): Imbalance between autoreactive and regulatory T cell activities has been considered a major mechanism in the development of autoimmune disease. Previous studies on regulatory T cells have focused mainly on ab T cell receptor (TCR) expressing cells, commonly referred to as Treg cells. Recent studies have identified Gammadelta T cells as major regulatory cells in immune responses against tumor, infections, and autoimmune diseases; furthermore, manipulation of Gammadelta T cell activity has a beneficial effect on various immune responses, suggesting that immunologic interventions acting on Gammadelta T cells are promising avenues for immunotherapy. Nevertheless, the mechanism of Gammadelta T cell regulation is more complicated than previously thought and Gammadelta T cells can either inhibit or enhance an immune response; however, the mechanism leading to the opposite regulatory effects is poorly understood, which hampers the therapeutic use. Exploiting our established working model in EAU in which Gammadelta T cells either suppress or enhance the uveitogenic T cell response, we propose to determine the mechanism by which Gammadelta T cells up- and down-regulate autoimmune diseases. We will test the hypothesis that the regulatory function of Gammadelta T cells differs when they are activated to varying degrees or activated via different pathways by determining whether Gammadelta cells activated via different pathways exert different regulatory effect on generation of uveitogenic T cells and by determining how Gammadelta T cells alter their regulatory effect as a result of interacting with dendritic cells (DCs), natural killer T cells (NKTs), and ab T cell (Aim1). We also propose to determine the mechanism by which Gammadelta T cells regulate by examining the conditions that convert the Gammadelta T cells' up- and down-regulatory activity; to determine the reciprocal interaction between Gammadelta and DCs and between ab and Gammadelta T cells; and to determine whether abTCR+ Treg cells and Gammadelta T cells differ in regulating Th1 and Th17 responses (Aim 2). The proposed studies will test our hypothesis that "the effects in Gammadelta T cells on immune responses are dynamic and can either be inhibitory or enhancing depending upon the activation status and size of the Gammadelta T cell population". Upon accomplishment of the study, the up- and down-regulatory effect of Gammadelta T cells should be better understood and we should be able to predict the relative role of differently activated Gammadelta T cells in the autoimmune responses with greater accuracy, which should greatly promote the establishment of a justified monitor system advising effective, Gammadelta-targeted immune-therapy. PUBLIC HEALTH RELEVANCE: Uveitis is a sight-threatening, inflammatory disease. Mice can be induced for similar disease, either by immunization with a pathogenic antigen or by adoptive transfer with uveitogenic T cells. Exploiting these experimental models we will determine the pathogenic mechanisms that is not possible to be directly examined in humans. The research goals of our laboratory are to characterize pathogenic T cells that cause this disease and to seek possible ways to prevent the disease development. Based on the finding that T cells expressing Gammadelta T cell receptor have a strong regulatory effect in the pathogenic response, we predict that manipulation of Gammadelta T cell activation can be used as tool for control the pathogenic activity of autoreactive T cells and autoimmune disease. However, the regulatory effect of Gammadelta T cell changes from time to time, which is affected by various environmental factors and is intimately related to activation and expansion of the Gammadelta T cells. We need, in the first place, to find out how Gammadelta T cells alter their activation statu in the body, and how differently activated Gammadelta T cells alter their regulatory effect, leading to enhanced or suppressed disease.

描述（由申请人提供）：自身反应性和调节性 T 细胞活性之间的不平衡已被认为是自身免疫性疾病发展的主要机制。此前对调节性T细胞的研究主要集中在ab T细胞受体（TCR）表达细胞，通常称为Treg细胞。最近的研究已确定 Gammadelta T 细胞是针对肿瘤、感染和自身免疫性疾病的免疫反应的主要调节细胞；此外，操纵 Gammadelta T 细胞活性对各种免疫反应具有有益的影响，这表明作用于 Gammadelta T 细胞的免疫干预是免疫治疗的有希望的途径。然而，Gammadelta T细胞的调节机制比之前想象的更为复杂，Gammadelta T细胞可以抑制或增强免疫反应；然而，人们对导致相反调节作用的机制知之甚少，这阻碍了治疗用途。利用我们在 EAU 中建立的工作模型（其中 Gammadelta T 细胞抑制或增强葡萄膜 T 细胞反应），我们建议确定 Gammadelta T 细胞上调和下调自身免疫性疾病的机制。我们将通过确定通过不同途径激活的 Gammadelta 细胞是否对产生葡萄膜的 T 细胞产生不同的调节作用以及确定 Gammadelta 如何发挥作用，来检验以下假设：当 Gammadelta T 细胞被激活到不同程度或通过不同途径激活时，其调节功能会有所不同。 T 细胞由于与树突状细胞 (DC)、自然杀伤 T 细胞 (NKT) 和 ab T 细胞 (Aim1) 相互作用而改变其调节作用。我们还建议通过检查改变 Gammadelta T 细胞上调和下调活性的条件来确定 Gammadelta T 细胞的调节机制；确定 Gammadelta 和 DC 之间以及 ab 和 Gammadelta T 细胞之间的相互作用；并确定 abTCR+ Treg 细胞和 Gammadelta T 细胞在调节 Th1 和 Th17 反应方面是否存在差异（目标 2）。拟议的研究将检验我们的假设，即“Gammadelta T 细胞对免疫反应的影响是动态的，并且可以是抑制性的，也可以是增强性的，具体取决于 Gammadelta T 细胞群的激活状态和大小”。研究完成后，我们应该更好地了解 Gammadelta T 细胞的上调和下调作用，并且我们应该能够更准确地预测不同激活的 Gammadelta T 细胞在自身免疫反应中的相对作用，这将大大促进建立合理的监测系统，建议有效的、针对 Gammadelta 的免疫治疗。 公共卫生相关性：葡萄膜炎是一种威胁视力的炎症性疾病。通过用致病性抗原进行免疫或用致葡萄膜 T 细胞进行过继转移，可以诱导小鼠患上类似的疾病。利用这些实验模型，我们将确定不可能在人类中直接检查的致病机制。我们实验室的研究目标是确定导致这种疾病的致病性 T 细胞的特征，并寻找预防疾病发展的可能方法。基于表达 Gammadelta T 细胞受体的 T 细胞在致病反应中具有很强的调节作用的发现，我们预测操纵 Gammadelta T 细胞活化可以作为控制自身反应性 T 细胞和自身免疫性疾病的致病活性的工具。然而，Gammadelta T细胞的调节作用时常发生变化，受到多种环境因素的影响，与Gammadelta T细胞的激活和扩增密切相关。首先，我们需要找出 Gammadelta T 细胞如何改变其在体内的激活状态，以及不同激活的 Gammadelta T 细胞如何改变其调节作用，从而导致疾病的增强或抑制。