On the plasticity of Beta-cell antigen recognition by diabetogenic CD8 T cells

致糖尿病 CD8 T 细胞识别 Beta 细胞抗原的可塑性

基本信息

批准号：
10445075
负责人：
Baoyu Liu
金额：
$ 15.25万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10445075
关键词：
Address Affinity Aging Anatomy Antigens Autoantigens Autoimmune Autoimmune Diseases Beta Cell Binding Biological Assay Biological Markers CD8-Positive T-Lymphocytes CD8B1 gene Cell Maturation Cells Characteristics Clone Cells Data Development Diabetes Mellitus Disease Event Frequencies G6PC2 gene Immune Immune system Individual Infiltration Insulin Insulin-Dependent Diabetes Mellitus Intervention Kinetics Label Location MHC Class I Genes MHC antigen Measurement Measures Methods Modeling Molecular Mouse Strains Nature Non obese Pancreas Pathogenesis Patients Peptide/MHC Complex Phenotype Play Population Property Role Stains T cell response T-Cell Activation T-Lymphocyte Techniques Technology Testing Thymus Gland Transgenic Organisms Virus autoreactive T cell base cytotoxic cytotoxicity diabetes pathogenesis diabetic diabetogenic experimental study glucose-6-phosphatase insight islet mechanical force mechanotransduction novel novel therapeutic intervention protein expression single cell analysis single molecule single-cell RNA sequencing thymocyte transcriptome

项目摘要

Project summary CD8 T cells play an essential role in T1D pathogenesis. They comprise the most abundant immune cell population in patient islet infiltrates. In the non-obese diabetic (NOD) model of T1D, they are required for diabetes development. The infiltration and retention of autoreactive T cells in islets is strictly dependent on specific recognition of beta-cell antigens. Such self-recognition also determines diabetogenic CD8 T cell’s cytotoxicity and ultimate killing of beta-cells. However, little is known about how CD8+ T cells recognize beta- cell antigens. Over the past decade, we have used novel 2D assays to characterize T cell antigen recognition in general, revealing 2D affinity and mechanical force as two defining kinetics parameters in determining T cell responses. In the current proposal, we will apply these 2D methods to beta-cell antigen recognition by autoimmune CD8 T cells and elucidate the underlying molecular mechanisms by single cell RNA sequencing. Our preliminary data show that diabetogenic CD8 T cells can greatly change affinity and/or force of self-antigen recognition depending on T cell maturation, activation, and disease status. We propose two specific aims to test a central hypothesis that diabetogenic CD8 T cells bind to beta-cell self-antigens weakly to evade tolerance mechanisms but can upregulate bond strength to drive disease. In Specific Aim 1, we will use our 2D methods to characterize affinity and force of beta-cell antigen recognition by CD8 T cells throughout the course of diabetes. In Specific Aim 2, we will use single cell transcriptome analysis to elucidate molecular mechanisms that abnormally regulate beta-cell self-antigen recognition. The project will generate critical yet currently missing information on beta-cell self-antigen recognition and inform novel intervention strategies that are capable of specifically targeting diabetogenic CD8 T cells.

项目概要 CD8 T 细胞在 T1D 发病机制中发挥重要作用，它们包含最丰富的免疫细胞。在 T1D 的非肥胖糖尿病 (NOD) 模型中，它们是必需的。糖尿病的发展严格取决于胰岛中自身反应性 T 细胞的浸润和保留。对 β 细胞抗原的特异性识别也决定了致糖尿病的 CD8 T 细胞的能力。然而，对于 CD8+ T 细胞如何识别 β- 细胞，人们知之甚少。在过去的十年中，我们使用新颖的 2D 分析来表征 T 细胞抗原识别。一般来说，揭示 2D 亲和力和机械力作为确定 T 细胞的两个定义动力学参数在当前的提案中，我们将通过以下方式将这些 2D 方法应用于 β 细胞抗原识别。自身免疫 CD8 T 细胞并通过单细胞 RNA 测序阐明潜在的分子机制。我们的初步数据表明，致糖尿病的 CD8 T 细胞可以极大地改变自身抗原的亲和力和/或作用力我们提出了两个具体目标来识别 T 细胞的成熟、激活和疾病状态。测试一个中心假设，即致糖尿病的 CD8 T 细胞与 β 细胞自身抗原微弱结合以逃避在特定目标 1 中，我们将使用我们的 2D。表征整个过程中 CD8 T 细胞对 β 细胞抗原识别的亲和力和力量的方法在具体目标 2 中，我们将使用单细胞转录组分析来阐明糖尿病的分子机制。异常调节β细胞自身抗原识别该项目目前将产生关键作用。缺失有关 β 细胞自身抗原识别的信息，并为新的干预策略提供信息能够特异性靶向致糖尿病的 CD8 T 细胞。