T cell repertoire for hybrid insulin peptides

项目摘要 1型糖尿病（T1 D）中驱动致病性T细胞应答的自身抗原的鉴定是一个重要的研究课题。 由于生物标志物发现和疾病的影响， 预防战略。我们的实验室专注于CD 4 T细胞在发病机制和调节中的作用 特别强调它们的靶抗原。使用蛋白质组学方法和BDC 一组CD 4 T细胞克隆作为我们的抗原检测系统，我们最近发现， 在我们的小组中激活几个克隆，包括原型克隆BDC-2.5，是通过一个 涉及在肽切割之间形成杂合肽的新的翻译后修饰 β-细胞蛋白质如ChgA或IAPP的产物和来自胰岛素C肽的序列。的发现 杂合胰岛素肽（HIP）作为一类新的新抗原引起了关于HIP的程度的问题 T1 D中的反应性以及对HIP反应的T细胞是否驱动自身免疫过程。我们假设 HIP反应性T细胞可以作为疾病的生物标志物， NOD小鼠和T1 D患者将提供在疾病发生前对其进行分期的新可能性。测试 基于这一假设，我们建议（1）研究T细胞对杂合胰岛素肽（HIP）的库， NOD小鼠;（2）在T1 D和高危小鼠中使用组合肽库发现C肽HIP反应性 受试者和（3）监测处于T1 D风险的受试者中HIP反应性T细胞随时间的表型和TCR。

Project Abstract Identification of the autoantigens that drive the pathogenic T cell response in type 1 diabetes (T1D) is a research goal of great importance because of the implications for biomarker discovery and disease prevention strategies. Our lab has focused on the role of CD4 T cells in both pathogenesis and regulation of disease with particular emphasis on their target antigens. Using a proteomic approach and the BDC panel of CD4 T cell clones as our antigen detection system, we recently discovered that the peptide ligands that activate several clones in our panel, including the prototype clone BDC-2.5, were formed through a novel post-translational modification involving formation of hybrid peptides between peptide cleavage products of -cell proteins such as ChgA or IAPP and sequences from insulin C-peptide. The discovery of hybrid insulin peptides (HIPs) as a new class of neoantigens raises questions as to the extent of HIP reactivity in T1D and whether T cells reactive to HIPs drive the autoimmune process. We hypothesize that HIP-reactive T cells can serve as biomarkers of disease and that the discovery of new HIP reactivities in NOD mice and patients with T1D will offer new possibilities to stage the disease before it occurs. To test this hypothesis, we propose to (1) investigate the T cell repertoire for hybrid insulin peptides (HIPs) in the NOD mouse; (2) discover C-peptide HIP reactivities using combinatorial peptide pools in T1D and at risk subjects and (3) monitor phenotype and TCR of HIP-reactive T cells over time in subjects at risk for T1D.