Autoantigens targeted by CD8 T cells in type 1 diabetes: from islets to blood

1 型糖尿病中 CD8 T 细胞靶向的自身抗原：从胰岛到血液

• 批准号: 10633104
• 负责人: AARON W MICHELS
• 金额: $ 53.28万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633104
• 关键词: Antigen Targeting; Antigens; Autoantigens; Beta Cell; Biological Markers; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Separation; Cells; Chromogranin A; Classification; Data; Development; Diabetes prevention; Disease; Epitopes; Frequencies; Glutamic Acid; Goals; HLA-A gene; Heterogeneity; Hot Spot; Hybrids; Immune; Immune Tolerance; Immune response; Immunotherapy; Individual; Infiltration; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Islets of Langerhans; Measures; Oral; Organ Donor; Pancreas; Pathogenesis; Patients; Peptide Library; Peptides; Peripheral; Phenotype; Post-Translational Protein Processing; Proinsulin; Proteins; Residual state; Risk; Specificity; T cell infiltration; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell inflamed; Testing; autoimmune pathogenesis; combinatorial; design; insight; insulin dependent diabetes mellitus onset; insulin secretion; islet; non-diabetic; novel; novel marker; patient subsets; peripheral blood; preproinsulin; prevent; response; screening; specific biomarkers; treatment responders; zinc-binding protein

Project Summary Identification of antigens that are involved in the pathogenesis of type 1 diabetes (T1D) is crucial to develop biomarkers and therapies for T1D. There have been recent efforts focused on identifying antigens recognized by T cells within the residual islets of T1D organ donors due to the premise that such T cells are likely to be involved in disease pathogenesis. Our preliminary data studying islet-infiltrating CD8 T cells demonstrates that a large proportion, 1/3 to 1/2 of T1D organ donors, are reactive to preproinsulin (PPI) peptides, whereas the remaining donors have only few or no PPI-reactive CD8 T cells in the islets. Epitopes recognized by the PPI- reactive CD8 T cells are presented by many HLA class I molecules spanning HLA-A, B, and C, and are spread throughout the PPI protein with several hot spots that are preferentially recognized by multiple T cell receptors (TCR) expressed by the T cells. Thus, preproinsulin is a major self-antigen and contains epitopes for T1D- associated CD8 T cells in a subset of T1D patients. Yet antigens targeted by islet-infiltrating T cells in the remaining patients exist outside PPI, suggesting heterogeneity in antigen specificity targeted by islet-resident CD8 T cells. Towards an ultimate goal of developing antigen-specific biomarkers and therapies for T1D, two important questions remain; (1) What antigens are recognized by islet-infiltrating CD8 T cells that do not react with PPI? (2) By measuring reactivity in peripheral blood, can we identify patients that have a particular antigen specificity in order to design appropriate therapy for each patient? The goal of this proposal is to uncover unknown antigen specificities recognized by islet-derived CD8 T cells and to evaluate the association between PPI reactivity in peripheral blood and the response to oral insulin as a proof of principle for personalized antigen- specific therapies. Our central hypothesis is that heterogeneity in self-antigen specificity for islet-derived CD8 T cells exists and determines the response to antigen-specific immunotherapy. If this hypothesis is correct, self- antigens targeted by CD8 T cells can be utilized to identify patients with particular antigen specificity to select for responders receiving antigen-specific immunotherapies for T1D prevention efforts. To test the hypothesis, we will identify antigens that are recognized by islet-infiltrating CD8 T cells either in a protein-targeted manner (Aim 1) and in an unbiased manner (Aim 2). Given our preliminary results that PPI is a major antigen for islet-infiltrating CD8 T cells in a subset of patients, we will focus on PPI to test whether there is an association between CD8 PPI reactivity and the response to oral insulin treatment (Aim 3). The successful completion of this proposal will result in identification of major self-antigens for islet-resident CD8 T cells in T1D patients. The identification of antigens can be used to classify heterogeneous T1D patients based on CD8 T cell antigen specificity with the goal to ultimately providing appropriate personalized antigen-specific immunotherapy for T1D prevention efforts.

项目摘要 鉴定参与1型糖尿病（T1D）发病机理的抗原对于发展至关重要 T1D的生物标志物和疗法。最近的工作重点是识别公认的抗原 由于T1D器官供体的残留胰岛内的T细胞是因为此类T细胞可能是 参与疾病发病机理。我们的初步数据研究胰岛渗透CD8 T细胞表明 T1D器官捐献者的1/3至1/2很大比例是对前胰岛素（PPI）肽的反应性的，而 其余的供体在胰岛中只有很少或没有PPI反应性CD8 T细胞。 ppi认可的表位 反应性CD8 T细胞由许多跨越HLA-A，B和C的HLA I类分子提出，并扩散 在整个PPI蛋白中，有几个热点，这些热点被多个T细胞受体识别 （TCR）由T细胞表达。因此，前胰岛素是一种主要的自我抗原，包含T1D-的表位 T1D患者子集中的相关CD8 T细胞。然而，由胰岛浸入T细胞靶向的抗原 剩余的患者存在于PPI之外，表明胰岛居民针对的抗原特异性异质性 CD8 T细胞。朝着开发T1D的抗原特异性生物标志物和疗法的最终目标，两个 仍然存在重要的问题； （1）通过不反应的胰岛浸润CD8 T细胞识别哪些抗原 和PPI？ （2）通过测量外周血的反应性，我们可以识别具有特定抗原的患者 为了为每个患者设计适当的治疗特异性吗？该提议的目的是发现 胰岛来源的CD8 T细胞识别的未知抗原特异性，并评估 PPI在外周血中的反应性和对口服胰岛素的反应作为个性化抗原的原理证明 具体疗法。我们的中心假设是，胰岛来源的CD8 T的自我抗原特异性异质性 细胞存在并确定对抗原特异性免疫疗法的反应。如果这个假设是正确的，那么自我 可以利用由CD8 T细胞靶向的抗原来鉴定具有特定抗原特异性的患者以选择 接受抗原特异性免疫疗法进行T1D预防工作的响应者。为了检验假设，我们 将以蛋白质靶向的方式鉴定通过渗入胰岛浸润CD8 T细胞识别的抗原（AIM 1）并以公正的方式（目标2）。鉴于我们的初步结果是PPI是胰岛渗透的主要抗原 CD8 T细胞在一部分患者中，我们将专注于PPI，以测试CD8之间是否存在关联 PPI反应性和对口服胰岛素治疗的反应（AIM 3）。该提案的成功完成将 导致T1D患者中胰岛驻留的CD8 T细胞的主要自我抗原鉴定。识别 抗原可用于基于CD8 T细胞抗原特异性的异质T1D患者 最终为T1D预防工作提供适当的个性化抗原特异性免疫疗法。

项目成果

Coxsackievirus infection induces direct pancreatic β-cell killing but poor anti-viral CD8+ T-cell responses.

柯萨奇病毒感染诱导直接胰腺β细胞杀伤，但抗病毒CD8 T细胞反应较差。

• DOI: 10.1101/2023.08.19.553954
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Vecchio,Federica;Carré,Alexia;Korenkov,Daniil;Zhou,Zhicheng;Apaolaza,Paola;Tuomela,Soile;Burgos-Morales,Orlando;Snowhite,Isaac;Perez-Hernandez,Javier;Brandao,Barbara;Afonso,Georgia;Halliez,Clémentine;Kaddis,John;Kent,SallyC;Na
• 通讯作者: Na