Autoimmune Stem-like CD8 T cells in Type 1 Diabetes

1 型糖尿病中的自身免疫干细胞样 CD8 T 细胞

基本信息

批准号：
10736295
负责人：
Andrea Schietinger
金额：
$ 91.07万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-08 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736295
关键词：
Antigen-Presenting Cells Autoimmune Autoimmune Diseases Bar Codes Beta Cell Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Communication Cells Complex DNA Equilibrium Gene Expression Profile Genes Goals Homing Human Image Inbred NOD Mice Individual Infiltration Insulin Insulin-Dependent Diabetes Mellitus Knowledge Maintenance Malignant Neoplasms Mediating Methods Modeling Molecular Molecular Target Mus Myeloid Cells Nature Non obese Organ Donor Pancreas Pathway interactions Patients Pattern Population Prevention Prevention strategy Risk Role Signal Transduction Site Stromal Cells T cell differentiation T cell receptor repertoire sequencing T cell response T cell transcription factor 1 T-Lymphocyte Testing Therapeutic Intervention WNT Signaling Pathway adult stem cell cellular targeting chemokine chronic infection clinical translation clinically relevant diabetes pathogenesis diabetic diabetogenic experimental study human disease immune cell infiltrate immunological synapse innovation innovative technologies insight lymph nodes migration mouse model multiplexed imaging novel peripheral blood population based prevent progenitor programs receptor self renewing cell self-renewal single-cell RNA sequencing stem stemness transcription factor

项目摘要

PROJECT SUMMARY T cell–mediated autoimmune diseases result from the breakdown of tolerance mechanisms in self-reactive CD8 T cells. However, many aspects of autoimmune CD8 T cell differentiation remain enigmatic, including where and how autoimmune T cell populations arise and are maintained and what molecular programs define autoimmune T cell states. Type I diabetes (T1D) is a CD8 T cell–mediated autoimmune disease; T1D pathogenesis is complex and involves immune infiltration of the pancreas and destruction of insulin-producing β cells by CD8 T cells. The non-obese diabetic (NOD) mouse model is a clinically relevant model of T1D, which shares many features with human disease. Utilizing the NOD model, we investigate autoimmune β cell-specific CD8 T cells differentiation state dynamics over the course of T1D. We identified a stem-like progenitor CD8 T cell population in the pancreatic lymph node that self-renews and gives rise to differentiated progeny, which migrate to the pancreas and destroy β cells. The goal of this application is to generate a deep mechanistic understanding of the niche- dependent intercellular interactions and signals in the pancreatic lymph node that maintain the autoimmune stem-like progenitor T cell pool and regulate differentiation, and to use this knowledge to develop strategies for therapeutic interventions. We will (i) employ innovative imaging and sequencing approaches to identify the spatial organization of pancreatic lymph node niches that determine diabetogenic T cell responses, (ii) determine the functional roles of key transcription factors controlling autoimmune T cell differentiation and test whether deletion or enforced expression of these transcription factors can alter autoimmune T cell states, and (iii) investigate autoimmune β cell-specific CD8 T cell states in human pancreatic lymph nodes and pancreas from organ donors with T1D. If successful, the proposed studies will provide important insights into autoimmune β cell-specific CD8 T cell programming in mouse and human T1D and could yield promising molecular and cellular targets for the prevention or treatment of T1D and other T cell-mediated autoimmune diseases.

项目概要 T 细胞介导的自身免疫性疾病是由自身反应性 CD8 耐受机制崩溃引起的然而，自身免疫性 CD8 T 细胞分化的许多方面仍然是个谜，包括在何处和如何分化。自身免疫 T 细胞群如何产生和维持以及哪些分子程序定义自身免疫 T 细胞状态。I 型糖尿病 (T1D) 是一种 CD8 T 细胞介导的自身免疫性疾病，其发病机制非常复杂。并涉及胰腺的免疫浸润和 CD8 T 细胞对产生胰岛素的 β 细胞的破坏。非肥胖糖尿病 (NOD) 小鼠模型是 T1D 的临床相关模型，与利用 NOD 模型，我们研究了自身免疫 β 细胞特异性 CD8 T 细胞分化。我们在 T1D 过程中发现了干细胞样祖细胞 CD8 T 细胞群。胰腺淋巴结自我更新并产生分化的后代，并迁移到胰腺并破坏 β 细胞该应用的目标是对利基产生深入的机制理解。胰腺淋巴结中依赖的细胞间相互作用和信号维持自身免疫干细胞样祖T细胞库并调节分化，并利用这些知识制定策略我们将 (i) 采用创新的成像和测序方法来识别确定致糖尿病 T 细胞反应的胰腺淋巴结微环境的空间组织，(ii) 确定控制自身免疫 T 细胞分化的关键转录因子的功能作用并测试是否这些转录因子的缺失或强制表达可以改变自身免疫 T 细胞状态，并且 (iii) 研究人胰腺淋巴结和胰腺中自身免疫 β 细胞特异性 CD8 T 细胞状态如果成功，拟议的研究将为自身免疫β提供重要的见解。在小鼠和人类 T1D 中进行细胞特异性 CD8 T 细胞编程，可能会产生有希望的分子和细胞预防或治疗 T1D 和其他 T 细胞介导的自身免疫性疾病的目标。