CD4+ T CELL PROFILES IN IDDM

决定CD4+T细胞活化和应答的主要因素是MHC-肽-TCR三分子相互作用所介导的信号强度。这种信号强度取决于三分子相互作用的密度和持续时间，可以用单个T细胞的“功能亲和力”来衡量。使用MHC四聚体的新技术现在可以用来量化多克隆T细胞群体的功能亲和力，我们建议使用这些技术来评估自身免疫性糖尿病患者的抗原特异性CD4+T细胞反应。我们假设，对多种胰岛自身抗原的高亲和力识别与疾病进展或较早发病相关。我们预测，在胰岛自身免疫的非进行性形式的受试者中，例如只有一种胰岛自身抗体的受试者，不会出现表位扩散和高亲和力反应。本计划项目中的高危和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。我们还将通过对受到各种共刺激或调节信号挑战的四聚体分类细胞的分析，检验自身反应性T细胞可能通过对下调无效而持续存在的假设。

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.