The Antigen Repertoire of CD4 T cells from Pancreatic Islets

胰岛 CD4 T 细胞的抗原库

• 批准号: 10503562
• 负责人: Maki Nakayama
• 金额: $ 49.37万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503562
• 关键词: Affinity; Alleles; Amino Acid Motifs; Antibodies; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoimmune Diseases; Automobile Driving; Bar Codes; Beta Cell; Biological; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cells; Clinical Trials Design; Computer Analysis; DNA; Development; Diabetes prevention; Disease; Disease Progression; Epitopes; Glutamate Decarboxylase; Goals; Grant; HLA-DR3 Antigen; HLA-DR4 Antigen; Health; Heterogeneity; Human; Hybridomas; Hybrids; Immune; Immunotherapy; Individual; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Link; MHC Class II Genes; Mass Spectrum Analysis; Organ Donor; Pancreas; Pathogenesis; Pathogenicity; Patients; Peptide Library; Peptides; Phenotype; Positioning Attribute; Process; Proinsulin; Protein Databases; Proteins; Risk; Source; Specificity; Spleen; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Tissues; Virus; antigen-specific T cells; autoimmune pathogenesis; cellular transduction; combinatorial; diabetes pathogenesis; diabetes risk; disease heterogeneity; genetic association; genomic locus; gut microbiome; improved; islet; islet autoimmunity; islet cell antibody; lymph nodes; molecular phenotype; non-diabetic; preproinsulin; prevent; response; transcriptome; zinc-binding protein

Project Summary Type 1 diabetes (T1D) is a tissue-specific autoimmune disorder. Strong genetic association with the HLA class II gene locus suggests the importance of CD4 T cells in initiating and driving the disease process. We and others have isolated T cells from the pancreas of T1D organ donors and identified T cell epitopes specific to insulin, and its precursor preproinsulin, as well as fusion peptides. An important next step is to elucidate the phenotypes of such islet-derived T cells in health and disease. Concurrently, the previous studies uncovered the fact that antigens for the majority of T cells in the islets are still unknown, and we do not even know whether those T cells are islet antigen-specific. Identifying antigen specificity of islet-CD4 T cells is critical to dissect disease pathogenicity and heterogeneity to develop antigen-specific immunotherapy to halt disease progression using appropriate antigens in a given individual. Therefore, the goal of this grant is to identify antigen specificity of CD4 T cells in the islets and link antigen-specific responses to T cell phenotypes. Multiple lines of evidence suggest that there may be `common' or preferred CD4 T cell epitopes within subsets of T1D patients. First, the vast majority of T1D patients have risk HLA class II alleles, and specific class II alleles are associated with development of an initial islet autoantibody (e.g. insulin autoantibodies develop in those with HLA-DR4, and glutamic acid decarboxylase-65 antibodies with HLA-DR3). Second, CD4 T cells having the same antigen specificity (e.g. proinsulin peptides and hybrid insulin peptides) are detected in the pancreata from multiple T1D organ donors, and the same reactivity is found in the blood of those with early stages of T1D. Finally, CD4 T cells specific to these epitopes have an inflammatory phenotype in the blood of T1D patients compared to non-diabetic controls. This leads us to hypothesize that islet autoimmunity is promoted and regulated by CD4 T cells reacting to `common' antigens that are shared by T1D patients having specific HLA class II molecules. We will determine the proportion of tissue-specific CD4 T cells in the islets (Aim 1) and seek to identify epitopes targeted by CD4 T cells in the islets of T1D organ donors (Aim 2). Furthermore, we will determine the molecular phenotype of islet antigen-specific T cells in the pancreatic lymph nodes and spleen of organ donors with and without T1D (Aim 3). The successful completion of this proposal will: (1) identify antigens and epitopes targeted by CD4 T cells from pancreatic islets across the stages of T1D development and (2) elucidate the molecular phenotype and features that render these T cells pathogenic. Thus, these studies will enhance our understanding of human T1D pathogenesis, dissect disease heterogeneity, and aid in improving the design of clinical trials evaluating antigen-specific immunotherapy for diabetes prevention.

项目摘要 1型糖尿病（T1 D）是一种组织特异性自身免疫性疾病。与HLA类有很强的遗传关联 II基因位点提示CD 4 T细胞在启动和驱动疾病过程中的重要性。我们和其他人 从T1 D器官捐赠者的胰腺中分离出T细胞，并鉴定出胰岛素特异性T细胞表位， 及其前体前胰岛素原，以及融合肽。下一步重要的工作是阐明 胰岛衍生T细胞在健康和疾病中的作用。同时，先前的研究揭示了这样一个事实， 胰岛中大多数T细胞的抗原仍然未知，我们甚至不知道这些T细胞是否 是胰岛抗原特异性的。识别胰岛-CD 4 T细胞的抗原特异性对于解剖疾病至关重要 致病性和异质性，以开发抗原特异性免疫疗法， 特定个体中的适当抗原。因此，该基金的目标是确定CD 4的抗原特异性， 胰岛中的T细胞，并将抗原特异性反应与T细胞表型联系起来。 多种证据表明，在亚群中可能存在“共同”或优选的CD 4 T细胞表位 T1 D患者首先，绝大多数T1 D患者具有风险HLA II类等位基因，并且特异性II类等位基因 与初始胰岛自身抗体的产生有关（例如，患有胰岛素自身抗体的人会产生胰岛素自身抗体） HLA-DR 4和谷氨酸脱羧酶-65抗体与HLA-DR 3）。第二，CD 4 T细胞具有相同的 在胰腺中检测到抗原特异性（例如胰岛素原肽和杂合胰岛素肽 多个T1 D器官捐赠者，在T1 D早期阶段的血液中发现了相同的反应性。 最后，特异于这些表位的CD 4 T细胞在T1 D患者的血液中具有炎性表型 与非糖尿病对照组相比。这使我们假设胰岛自身免疫被促进， 由与具有特异性HLA的T1 D患者共有的“共同”抗原反应的CD 4 T细胞调节 II类分子。我们将确定胰岛中组织特异性CD 4 T细胞的比例（目的1），并寻求 以鉴定T1 D器官供体胰岛中CD 4 T细胞靶向的表位（目的2）。此外，我们将 确定胰腺淋巴结和脾脏中胰岛抗原特异性T细胞的分子表型， 有和没有T1 D的器官捐献者（目标3）。成功完成这项建议将：（1）确定抗原 和在T1 D发展的各个阶段由来自胰岛的CD 4 T细胞靶向的表位，和（2） 阐明使这些T细胞致病的分子表型和特征。这些研究将 提高我们对人类T1 D发病机制的理解，剖析疾病异质性，并帮助改善 设计临床试验评估抗原特异性免疫疗法预防糖尿病。