T cell repertoire for hybrid insulin peptides

项目摘要 识别驱动1型糖尿病(T1D)病理性T细胞反应的自身抗原是一种 研究目标非常重要，因为它对生物标记物的发现和疾病有影响 预防策略。我们的实验室重点研究了CD4T细胞在发病机制和调节中的作用 特别强调它们的目标抗原。使用蛋白质组学方法和BDC 作为我们的抗原检测系统，我们最近发现CD4T细胞的多肽配体 在我们的面板中激活了几个克隆，包括原型克隆BDC-2.5，是通过 一种新的翻译后修饰，涉及在多肽裂解之间形成杂交肽 细胞蛋白的产物，如ChgA或IAPP和来自胰岛素C肽的序列。发现了 杂合胰岛素肽(HIPS)作为一类新的新抗原，引起了人们对HIP程度的质疑。 T1D的反应性以及T细胞是否对HIPS起反应推动了自身免疫过程。我们假设 髋关节反应性T细胞可以作为疾病的生物标志物，新的髋关节反应性的发现 NOD小鼠和患有T1D的患者将提供新的可能性，在疾病发生之前将其分期。为了测试 在这一假设下，我们建议：(1)研究混合胰岛素多肽(HIPS)的T细胞谱系。 NOD小鼠；(2)在T1D和面临风险的情况下，使用组合肽库发现C-肽HIP反应 受试者和(3)监测T1D风险受试者随时间变化的髋关节反应性T细胞的表型和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.