CD4+ T CELL PROFILES IN IDDM

IDDM 中的 CD4 T 细胞谱

• 批准号: 7468454
• 负责人: GERALD T NEPOM
• 金额: $ 26.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468454
• 关键词: Accounting; Affinity; Alleles; Antigens; Attention; Autoantibodies; Autoantigens; Autoimmune Diabetes; Autoimmunity; Avidity; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; Cell Death; Cell Separation; Cells; Class; Clinical; Data; Diabetes Mellitus; Disease; Disease Progression; Down-Regulation; Epitopes; Event; HLA-DR4 Antigen; Human; Immune; Immunity; Immunologics; Individual; Insulin-Dependent Diabetes Mellitus; Ligands; Measures; Mediating; Monitor; Numbers; Onset of illness; Pathogenesis; Pathway interactions; Patients; Peptide/MHC Complex; Peripheral; Personal Satisfaction; Phase; Phenotype; Population; Population Study; Prevalence; Proliferating; Property; Proteins; Refractory; Regulation; Research Personnel; Resistance; Risk; Screening procedure; Signal Transduction; Specificity; Staging; Stimulus; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Epitopes; TCR Activation; Techniques; Testing; autoreactive T cell; base; cohort; density; early onset; human subject; interest; islet; new technology; peripheral blood; pre-clinical; programs; response; tool

A major determinant of CD4+ T cell activation and response is the strength of signal mediated by the trimolecular MHC-peptide-TCR interaction. This strength of signal is dependent on the density and duration of trimolecular interactions, and can be measured in terms of "functional avidity" for individual T cells. New technologies using MHC tetramers are now available to quantify functional avidity in a polyclonal T cell population, and we propose to use these techniques to evaluate the antigen-specific CD4+ T cell response in autoimmune diabetes. We hypothesize that high avidity recognition of multiple islet autoantigens correlates with disease progression or earlier disease onset. We predict that epitope spreading and high avidity responses fail to occur in subjects with non-progressive forms of islet autoimmunity, such as subjects with only a single islet autoantibody. At-risk and LADA cohorts in this program project will be compared to T1D subjects, and integrated with the autoantibody progression studies in Project 2. we will also test the hypothesis that autoreactive T cells may persist by becoming refractory to down-regulation, through the analysis of tetramer-sorted cells challenged with a variety of costimulatory or regulatory signals.

CD4+ T 细胞激活和反应的主要决定因素是三分子 MHC-肽-TCR 相互作用介导的信号强度。这种信号强度取决于三分子相互作用的密度和持续时间，并且可以根据单个 T 细胞的“功能亲和力”来测量。使用 MHC 四聚体的新技术现在可用于量化多克隆 T 细胞群的功能亲合力，我们建议使用这些技术来评估自身免疫糖尿病中抗原特异性 CD4+ T 细胞反应。我们假设多种胰岛自身抗原的高亲和力识别与疾病进展或早期疾病发作相关。我们预测表位扩散和高亲和力反应不会发生在具有非进行性形式的胰岛自身免疫的受试者中，例如仅具有单一胰岛自身抗体的受试者。该项目中的高危人群和 LADA 队列将与 T1D 受试者进行比较，并与项目 2 中的自身抗体进展研究相结合。我们还将通过分析受到各种共刺激或调节信号挑战的四聚体分类细胞，检验自身反应性 T 细胞可能因难以下调而持续存在的假设。