T cell repertoire for hybrid insulin peptides

混合胰岛素肽的 T 细胞库

• 批准号: 10170349
• 负责人: KATHRYN M HASKINS
• 金额: $ 49.27万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170349
• 关键词: Antigen Targeting; Antigens; Applications Grants; Autoantigens; Autoimmune Diabetes; Autoimmune Process; Autoimmunity; Biological Assay; Biological Markers; C-Peptide; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line; Cells; Chromogranin A; Clone Cells; Disease; Disease Progression; Epitopes; Frequencies; Gene Expression; Genomics; Goals; Human; Hybrids; Inbred NOD Mice; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Ligands; Longitudinal Studies; Monitor; N-terminal; Paper; Pathogenesis; Pathogenicity; Patients; Peptide Library; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Post-Translational Protein Processing; Prevention strategy; Proteins; Proteomics; Publishing; Regulation; Research; Research Personnel; Risk; Role; Science; Source; System; T cell response; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Time; Work; antigen detection; biomarker discovery; combinatorial; design; detection platform; diabetic patient; diabetogenic; disorder prevention; enzyme linked immunospot assay; human subject; in vivo; islet; islet amyloid polypeptide; neoantigens; novel; peripheral blood; protein aminoacid sequence; prototype; screening; single-cell RNA sequencing; transcriptomics

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.

项目摘要 识别驱动 1 型糖尿病 (T1D) 致病性 T 细胞反应的自身抗原是一项重要任务 由于对生物标志物发现和疾病的影响，研究目标非常重要 预防策略。我们的实验室重点研究 CD4 T 细胞在发病机制和调节中的作用 疾病的诊断，特别强调其靶抗原。使用蛋白质组方法和 BDC CD4 T 细胞克隆组作为我们的抗原检测系统，我们最近发现肽配体 激活我们面板中的几个克隆，包括原型克隆 BDC-2.5，是通过 新颖的翻译后修饰涉及肽裂解之间杂合肽的形成  细胞蛋白的产物，例如 ChgA 或 IAPP 以及胰岛素 C 肽的序列。的发现 混合胰岛素肽（HIP）作为一类新的新抗原引发了关于 HIP 范围的问题 T1D 的反应性以及 T 细胞对 HIP 的反应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，新的 HIP 反应性的发现 NOD 小鼠和 T1D 患者将为在疾病发生之前对疾病进行分期提供新的可能性。测试 根据这一假设，我们建议 (1) 研究混合胰岛素肽 (HIP) 的 T 细胞库 诺德鼠标； (2) 使用 T1D 和处于危险中的组合肽池发现 C 肽 HIP 反应性 (3) 监测有 T1D 风险的受试者中 HIP 反应性 T 细胞随时间的表型和 TCR。