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

• 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
• 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

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.

项目摘要 T细胞介导的自身免疫性疾病是由于自身反应性CD 8 T细胞。然而，自身免疫性CD 8 T细胞分化的许多方面仍然是谜，包括在哪里和 自身免疫性T细胞群是如何产生和维持的，以及什么样的分子程序定义了自身免疫性T细胞群 T细胞状态。I型糖尿病（T1 D）是一种CD 8 T细胞介导的自身免疫性疾病，发病机制复杂 并且涉及胰腺的免疫浸润和CD 8 T细胞对产生胰岛素的β细胞的破坏。的 非肥胖糖尿病（NOD）小鼠模型是T1 D的临床相关模型，其与T1 D小鼠模型共享许多特征。 人类疾病利用NOD模型，我们研究了自身免疫性β细胞特异性CD 8 T细胞分化 在T1 D过程中的状态动态。我们发现，干细胞样祖细胞CD 8 T细胞群在CD 8 T细胞中， 自我更新并产生迁移到胰腺的分化后代的胰腺淋巴结 破坏β细胞这个应用程序的目标是产生一个深刻的机械理解的利基- 胰腺淋巴结中的依赖性细胞间相互作用和信号， 干细胞样祖细胞T细胞库和调节分化，并利用这些知识来开发策略， 治疗干预。我们将（i）采用创新的成像和测序方法来识别 胰腺淋巴结小生境的空间组织，其决定致糖尿病性T细胞应答，（ii）确定 控制自身免疫性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性T细胞状态，以及（iii） 研究人胰腺淋巴结和胰腺中自身免疫性β细胞特异性CD 8 T细胞状态 T1 D的器官捐献者如果成功的话，这些研究将为自身免疫性β 在小鼠和人T1 D中的细胞特异性CD 8 T细胞编程，并且可以产生有前景的分子和细胞生物学特性。 用于预防或治疗T1 D和其他T细胞介导的自身免疫性疾病的靶点。