2D kinetics of antigen recognition in the CNS

CNS 中抗原识别的二维动力学

• 批准号: 10166961
• 负责人: Brian D Evavold
• 金额: $ 33.36万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166961
• 关键词: Address; Affinity; Alleles; Animal Model; Anti-Inflammatory Agents; Antigens; Area; Autoantigens; Autoimmune; Autoimmune Diseases; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cell Cycle Kinetics; Cell membrane; Cell physiology; Cells; Cholesterol; Complex; DNA; Data; Defect; Demyelinating Diseases; Demyelinations; Dietary Fats; Dietary Fatty Acid; Disease; Elements; Environment; Experimental Autoimmune Encephalomyelitis; Fish Oils; Funding; Goals; Inflammatory Response; Kinetics; Length; Ligands; MHC Interaction; Measures; Mediating; Membrane; Modeling; Myelin; Neuraxis; Onset of illness; Outcome; Pathogenicity; Pathway interactions; Peptide/MHC Complex; Peptides; Peripheral; Phenotype; Population; Process; Proteins; Publishing; Relapse; Reporting; Research; Risk Factors; Role; Severity of illness; Signal Pathway; Signal Transduction; Supplementation; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TCR Activation; Technology; Testing; Time; Tissues; Work; antigen-specific T cells; autoreactive T cell; base; dietary; effector T cell; expectation; experimental study; innovation; insight; multiple sclerosis patient; novel; oligodendrocyte-myelin glycoprotein; receptor binding; response; two-dimensional

Abstract/Summary Although every T cells recognizes and interacts with self-antigens, it is unknown why only some T cells cause autoimmune disease. HLA class II alleles have been identified as the number one risk factor in MS as well several other autoimmune diseases. Because MHC molecules present peptide antigens to create the antigenic ligand for T cell receptors (TCR), some breakdown in antigen recognition is responsible for autoimmune disease. However, the defects in antigen recognition are unknown. Our work seeks to determine the process of antigen recognition by autoimmune T cells from the CNS by defining the two dimensional (2D) binding kinetics of TCR for myelin peptide:MHC (pMHC). This renewal R01, builds on our published work from the last funding cycle that defined how 2D affinity of myelin oligodendrocyte glycoprotein (MOG)-specific populations related to EAE induction. Now we will determine what dictates the lifetime of antigen recognition. The bond lifetime of TCR interaction with pMHC is a novel and exciting area of research because we, and others, have found that the dynamic activities of T cells apply force to the APC resulting in alteration the length of time of antigen recognition. Importantly, bond lifetime determines T cell activation and dictates their fate - our work and that of others show it is absolutely required for optimal T cell function. Our preliminary data demonstrates that MOG-specific T cells from the CNS have greatly increased bond lifetime as compared to the cells in the periphery. This is in contrast to foreign antigen specific T cells that demonstrate no difference in force induced bond lifetimes on activation. For this renewal application we have generated compelling preliminary data using several unique technologies and animal models. Moreover, we apply these technologies to define the process of self-antigen recognition in the CNS. Together, the proposed work will fully define the bond lifetime under force that occurs between TCR and MOG self-antigens from naïve peripheral to active effector T cells in the CNS. The innovative insights generated by continuation of our work will provide the base understanding of T cell activation that permits demyelinating disease. The work will be undertaken through 3 specific aims that will: 1) Define 2D force-induced changes in bond lifetimes during demyelinating disease 2) Define the magnitude and mechanisms by which CD4 T cells generate force 3) Delineate dietary fatty acid impact on TCR:myelin 2D kinetics

摘要/概要 尽管每个T细胞都能识别自身抗原并与之相互作用，但目前尚不清楚为什么只有一些T细胞能识别自身抗原并与之相互作用。 导致自身免疫性疾病。HLA II类等位基因已被确定为头号风险 多发性硬化症以及其他几种自身免疫性疾病的因素。因为MHC分子呈递肽 抗原产生T细胞受体（TCR）的抗原配体，抗原中的一些分解 识别是自身免疫性疾病的原因然而，抗原识别的缺陷是 未知我们的工作旨在确定自身免疫T细胞识别抗原的过程 通过定义TCR对髓鞘肽：MHC的二维（2D）结合动力学， （pMHC）。本次更新R01建立在我们上一个资助周期的已发表工作的基础上， 与EAE相关的髓鞘少突胶质细胞糖蛋白（MOG）特异性群体的2D亲和力 诱导现在我们将确定是什么决定了抗原识别的寿命。债券寿命 TCR与pMHC的相互作用是一个新的和令人兴奋的研究领域，因为我们和其他人， 发现T细胞的动态活动对APC施加力，导致APC的长度改变， 抗原识别时间。重要的是，键寿命决定T细胞活化，并决定它们的 命运-我们的工作和其他人的工作表明它是最佳T细胞功能所必需的。我们 初步数据表明，来自CNS的MOG特异性T细胞大大增加， 键寿命与周边的电池相比。这与外来抗原相反 这些特异性T细胞在激活时证明力诱导的键寿命没有差异。 对于此更新应用程序，我们使用几种独特的方法生成了令人信服的初步数据 技术和动物模型。此外，我们应用这些技术来定义 CNS中的自身抗原识别。总之，拟议的工作将充分界定债券的生命周期 在TCR和MOG自身抗原之间发生的力下，从幼稚外周到活性效应子 CNS中的T细胞。我们继续开展工作所产生的创新见解将提供 对T细胞活化导致脱髓鞘疾病的基本认识。这项工作将 通过三个具体目标开展，这些目标将： 1)定义脱髓鞘疾病期间键寿命的2D力诱导变化 2)定义CD4 T细胞产生力的大小和机制 3)描绘膳食脂肪酸对TCR的影响：髓鞘2D动力学