CD4+ T CELL PROFILES IN IDDM

CD4+ T细胞活化和应答的主要决定因素是三分子mhc肽- tcr相互作用介导的信号强度。这种信号强度取决于三分子相互作用的密度和持续时间，并且可以根据单个T细胞的“功能亲和度”进行测量。使用MHC四聚体的新技术现在可用于量化多克隆T细胞群体的功能亲和性，我们建议使用这些技术来评估自身免疫性糖尿病中抗原特异性CD4+ T细胞的反应。我们假设对多种胰岛自身抗原的高度识别与疾病进展或早期发病有关。我们预测，表位扩散和高贪婪反应不会发生在非进行性胰岛自身免疫的受试者中，例如只有单一胰岛自身抗体的受试者。本项目中的高危和LADA队列将与T1D受试者进行比较，并与项目2中的自身抗体进展研究相结合。我们还将通过分析受到各种共刺激或调节信号挑战的四聚体分类细胞，来验证自身反应性T细胞可能通过变得难以下调而持续存在的假设。

A major determinant of CD4+ T cell activation and response is the strength of signal mediated by the trimolecular MHC-peptide-TCR interaction. This strength of signal is dependent on the density and duration of trimolecular interactions, and can be measured in terms of "functional avidity" for individual T cells. New technologies using MHC tetramers are now available to quantify functional avidity in a polyclonal T cell population, and we propose to use these techniques to evaluate the antigen-specific CD4+ T cell response in autoimmune diabetes. We hypothesize that high avidity recognition of multiple islet autoantigens correlates with disease progression or earlier disease onset. We predict that epitope spreading and high avidity responses fail to occur in subjects with non-progressive forms of islet autoimmunity, such as subjects with only a single islet autoantibody. At-risk and LADA cohorts in this program project will be compared to T1D subjects, and integrated with the autoantibody progression studies in Project 2. we will also test the hypothesis that autoreactive T cells may persist by becoming refractory to down-regulation, through the analysis of tetramer-sorted cells challenged with a variety of costimulatory or regulatory signals.