T cell Heterogeneity and Fate Diversification in Autoimmune Type I Diabetes

自身免疫性 I 型糖尿病中 T 细胞异质性和命运多样化

• 批准号: 10227182
• 负责人: Sofia Vaccarino Gearty
• 金额: $ 5.1万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-14 至 2023-08-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227182
• 关键词: Antigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Automobile Driving; B-Lymphocyte Differentiation Antigens; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Characteristics; Complex; Development; Disease; Exhibits; G6PC2 gene; Gene Expression Profile; Genetic; Heterogeneity; High-Throughput RNA Sequencing; Inbred NOD Mice; Incidence; Infiltration; Informal Social Control; Insulin; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Investigation; Lymphoid Tissue; Maintenance; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Out-Migrations; Pancreas; Pathogenesis; Pharmacology; Phenotype; Physicians; Population; Population Heterogeneity; Prevention; Process; Production; Role; Scientist; Signal Transduction; T cell response; T-Lymphocyte; Testing; Therapeutic Intervention; Training; Tumor-infiltrating immune cells; autoreactive T cell; blood glucose regulation; cell killing; clinically relevant; differential expression; draining lymph node; experimental study; histological image; human disease; in vivo; insight; loss of function; lymph nodes; molecular targeted therapies; mouse model; novel; population based; progenitor; programs; self-renewal; single-cell RNA sequencing; spatiotemporal; stem cell function; stem-like cell; transcription factor; transcriptomics

Project Summary Type I diabetes (T1D) is a T cell-mediated autoimmune disease which is dramatically increasing in incidence. The pathogenesis of T1D is complex and incompletely understood, involving progressive destruction of pancreatic insulin-producing b cells by CD8 T cells, which leads to insulin deficiency and loss of glucose homeostasis. However, many aspects of the programming and regulation of self-reactive CD8 T cells mediating autoimmunity remain enigmatic. Utilizing the clinically relevant non-obese diabetic (NOD) mouse model of T1D, I investigated the activation and differentiation of b cell antigen-specific CD8 T cells throughout the course of T1D. I found that antigen-specific CD8 T cells exhibited phenotypic heterogeneity in the pancreatic draining lymph node (pLN) and in the pancreas. The specific hypothesis of this proposal is that the pancreatic autoimmune CD8 T cell response in T1D is driven by heterogeneous populations arising in the pLN. In this study, I will define the spatiotemporal factors that determine CD8 T cell population heterogeneity and identify transcription factor networks that define distinct autoimmune T cell populations in the pLN and pancreas in T1D. High-throughput RNA sequencing, in vivo gain and loss of function studies, and pharmacologic modulation experiments will be performed to determine the phenotypic, functional, and molecular characteristics of antigen- specific autoimmune CD8 T cells. Single-cell RNA sequencing will be employed to define population heterogeneity. This proposal is tailored for a physician-scientist in training, as it investigates the molecular mechanisms underlying a human disease and may identify promising molecular targets for the prevention or treatment of T1D and other T cell-mediated autoimmune diseases.

项目摘要 I型糖尿病（T1D）是一种T细胞介导的自身免疫性疾病，其发病率急剧增加。 T1D的发病机制复杂且不完全清楚，涉及对T1D细胞的进行性破坏。 胰腺产生胰岛素的B细胞通过CD8 T细胞，这导致胰岛素缺乏和葡萄糖损失 体内平衡。然而，自身反应性CD8 T细胞介导的自身反应性CD8 T细胞的编程和调节的许多方面是不确定的。 自身免疫仍然是个谜。利用T1D的临床相关非肥胖糖尿病（NOD）小鼠模型， 我研究了B细胞抗原特异性CD8 T细胞的活化和分化， T1D我发现抗原特异性CD8 T细胞在胰腺引流中表现出表型异质性， 淋巴结（pLN）和胰腺中。这个建议的具体假设是，胰腺 T1D中的自身免疫CD8 T细胞应答由pLN中产生的异质群体驱动。在 在这项研究中，我将定义决定CD8 T细胞群体异质性的时空因素， 在T1D的pLN和胰腺中定义不同的自身免疫T细胞群的转录因子网络。 高通量RNA测序、体内功能获得和丧失研究以及药理学调节 将进行实验以确定抗原的表型、功能和分子特征， 特异性自身免疫CD8 T细胞。将采用单细胞RNA测序来定义群体 异质性这个建议是专为一个医生，科学家在培训，因为它调查的分子 研究人类疾病的潜在机制，并可能确定有希望的分子靶点，用于预防或 治疗T1D和其他T细胞介导的自身免疫性疾病。