CD8+ T Cells Control Autoimmunity In EAE

CD8 T 细胞控制 EAE 中的自身免疫

• 批准号: 7083397
• 负责人: HONG JIANG
• 金额: $ 36.23万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7083397
• 关键词: MHC class II antigen; T cell receptor; antigen presenting cell; autoimmunity; cell cell interaction; cytotoxic T lymphocyte; experimental allergic encephalomyelitis; helper T lymphocyte; immunopathology; immunoregulation; intermolecular interaction; laboratory mouse; molecular cloning; polymerase chain reaction; protein binding; suppressor T lymphocyte

The goals and aims of the grant are based on previous studies showing that Qa-1 dependent CD8+ T cells play a major role in regulating peripheral self-reactive TCR repertoire by selectively down-regulating potentially pathogenic self-reactive T cells in EAE. The molecular interaction between the regulatory CD8+ T cells and target CD4+ T cells is through the recognition of Qa-1/self-peptide complex expressed on certain CD4+ T cells by the ab TCR on regulatory CD8+ T cells. Our observations lead us to propose an "affinity model" of peripheral T cell regulation by the regulatory CD8+ T cells. Basically, the affinity model proposes that whether or not a CD4+ T cell expresses Qa-1/self-peptide on their surface to induce and be specifically regulated by CD8+ T cells is dependent on the affinity of their TCR interaction with antigen/MHC class II complex on APCs during the initial antigen triggering. In this regard, it is known that following T cell activation the diversity of peptides bound to Qa-1 increases so that the activated T cells express Qa-1 molecules not only bound to the canonical Qa-1 binding peptide, Qdm, but also to self peptides induced by T cell activation. We hypothesize that these new Qa-1/self-peptide complexes are recognized by the CD8+ T cells which then differentiate to down-regulate activated CD4+ T cells expressing the same Qa-1/selfpeptide/ s. In this grant we will identify and test Qa-1 binding peptide/s which render the activated T cells susceptible to the down-regulation by the CD8+ T cells in EAE model. We will also 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. In addition, we will characterize the immune functions of the Qa-1 dependent CD8+ T cells in EAE by identifying the TCR Va and Vb repertoire of the CD8+ T cells and defining the other immunologic functions mediated by CD8+ T cells. The overall goal of this grant is to understand not only the theoretical basis of the immuno-regulatory pathway mediated by the Qa-1 dependent CD8+ T cells in control of auto-immunity but also the potential application of this pathway in treating auto-immune disease. In this regard, our studies will provide new insight into the general biology of peripheral T cell regulation and basic mechanisms by which the immune system could be manipulated to specifically suppress potentially pathogenic auto-immune responses.

赠款的目标和目标是基于以前的 研究表明，通过选择性地下调EAE中潜在的病原性自反应性T细胞，依赖性质量固定会依赖于CD8+ T细胞在调节外周外自反应TCR库中起着重要作用。调节性CD8+ T细胞与靶CD4+ T细胞之间的分子相互作用是通过AB TCR在调节性CD8+ T细胞上对某些CD4+ T细胞表达的QA-1/自肽复合物的识别。我们的观察结果使我们提出了通过调节性CD8+ T细胞调节周围T细胞调节的“亲和力模型”。基本上，亲和力模型提出，CD4+ T细胞是否在其表面表达QA-1/自肽以诱导并由CD8+ T细胞特别调节，这取决于其TCR相互作用与抗原/MHC类II的亲和力在初始抗原触发过程中对APC的II复合物。在这方面，众所周知，随着T细胞的激活，与QA-1结合的肽的多样性增加，因此活化的T细胞不仅表达与规范的QA-1结合肽QDM结合的QA-1分子，还与T细胞激活诱导的自肽。我们假设这些新的QA-1/自肽复合物是由CD8+ T细胞识别的，然后将表达相同QA-1/Selfpeptide/Selfpeptide/Selfselpeptide/Selfsive的激活的CD4+ T细胞区分化 s。在这笔赠款中，我们将识别和测试QA-1结合肽/S，从而呈现活化的T细胞 在EAE模型中，CD8+ T细胞易受CD8+ T细胞下调的影响。我们还将确定 EAE模型中自我反应性T细胞的亲和力/亲和力/亲和力和致病性之间的关系，进一步了解如何通过QA-1依赖的CD8+ T细胞对某些亲和力/亲和力克隆的优先降低调节，可提供一种控制围绕periphery的致病性自动免疫性的机制。此外，我们将通过识别CD8+ T细胞的TCR VA和VB曲目并定义由CD8+ T细胞介导的其他免疫功能，来表征EAE中QA-1依赖CD8+ T细胞的免疫功能。该赠款的总体目标不仅是理解由Qa-1依赖的CD8+ T细胞介导的免疫调节途径的理论基础，从而控制了自身免疫性，而且还可能在治疗自身免疫性疾病中的潜在应用。在这方面，我们的研究将提供有关外围T细胞调节的一般生物学和可以操纵免疫系统的基本机制的一般生物学的新见解，以专门抑制潜在的致病自身免疫反应。