Acute infection overrides PDL-1 mediated T cell suppression in autoimmune DM

在自身免疫性 DM 中，急性感染克服了 PDL-1 介导的 T 细胞抑制

• 批准号: 8279340
• 负责人: Jared H. Rowe
• 金额: $ 4.22万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279340
• 关键词: Acute; Affect; Antigen-Presenting Cells; Apoptosis; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; Cells; Cessation of life; Chronic; Cytokine Receptors; Defect; Diabetes Mellitus; Disease; Environmental Risk Factor; Epidemiology; Genetic; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunotherapy; Incidence; Individual; Infection; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Ligands; Listeria monocytogenes; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Non obese; Onset of illness; Organ; Pathway interactions; Patients; Predisposition; Prevention; Prevention therapy; Process; Role; Signal Transduction; Structure of beta Cell of islet; T-Cell Activation; T-Lymphocyte; Testing; Viral Tumor Antigens; base; cell type; cytokine; design; exhaustion; in vivo Model; mortality; mouse model; non-genetic; novel; pathogen; prevent; programs; research study

DESCRIPTION (provided by applicant): The mammalian immune system contains multiple intricately regulated networks of opposing stimulatory and inhibitory signals that together allow protective pathogen-specific immunity to be rapidly mobilized during infection while simultaneously quenching self-reative immune responses that can result in autoimmunity. Interestingly while the molecules that comprise these immune stimulatory or inhibitory networks are now being defined, the biological basis for how and why organ specific autoimmune disease occurs and the signals that cause breakdown in immune tolerance to self-antigens during autoimmunity remains largely unknown. In the well-characterized Non-obese diabetes (NOD) model of type I diabetes, immune tolerace that prevents the onset of islet cell desctuction is mediated in large part by T cell suppression through program cell death ligand-1 (PDL-1). Simarily PDL-1-medated suppression maintains T cell exhaustion in numerous models of chronic infection. However in sharp contrast, our recent studies using primary Listeria monocytogenes infeciton indicate that these PDL-1-mediated suppressive signals are re-programmed into T cell stimulation signals during acute infection conditions. These results combined with the epidemiological observation that most cases of type 1 diabetes are triggered by non-specific infectious illness suggest that acute infection through re-programming the normally suppressive effects of PDL-1 to self-antigen may trigger autoimmune diabetes. Accordingly in this application, we propose to examine the mechanistic basis for how acute infection reverses PDL-1 mediated T cell suppression and test the consequences of reversing PDL-1 function in a mouse model of autoimmune diabetes. Aim 1 of this application will explore roles of specific inflammatory cytokines in reprogramming PDL-1 function using mice with individual or combined defects in specific cytokine or cytokine receptors. Aim 2 of this application will examine the specific immune cell type(s) that PDL-1 acts on to confer either T cell stimulatory or inhibitory effects using cells isolated from PDL-1 deficient mice. Lastly, experiments outlined in aim 3 will directly test how acute infection, and the role of specific cytokines and immune cells described in the first two aims, reverses PDL-1 mediated tolerance using diabetes susceptible NOD mice. The results of these experiments will provide a mechansitic explanation for how autoimmunity is triggered in susceptible individuals, and more importantly elucide the specific immune cytokines and cells involved in this process allowing more rational prevention and immunotherapies for type 1 diabetes.

描述（由申请人提供）： 哺乳动物的免疫系统包含多个错综复杂的调节网络，这些网络由相反的刺激和抑制信号组成，这些网络共同允许在感染过程中快速动员保护性病原体特异性免疫，同时淬灭可能导致自身免疫的自身免疫反应。有趣的是，虽然组成这些免疫刺激或抑制网络的分子现在正在被定义，但器官特异性自身免疫性疾病如何以及为何发生的生物学基础，以及在自身免疫过程中导致对自身抗原的免疫耐受性崩溃的信号仍然很大程度上未知。在 I 型糖尿病的典型非肥胖糖尿病 (NOD) 模型中，防止胰岛细胞破坏发生的免疫耐受在很大程度上是通过程序细胞死亡配体 1 (PDL-1) 的 T 细胞抑制介导的。同样，PDL-1 介导的抑制在多种慢性感染模型中维持 T 细胞耗竭。然而，与此形成鲜明对比的是，我们最近使用原代单核细胞增生李斯特菌感染进行的研究表明，这些 PDL-1 介导的抑制信号在急性感染条件下被重新编程为 T 细胞刺激信号。这些结果与流行病学观察相结合，即大多数 1 型糖尿病病例是由非特异性感染性疾病引发的，这表明，通过将 PDL-1 的正常抑制作用重新编程为自身抗原，急性感染可能会导致急性感染。 引发自身免疫性糖尿病。因此，在本申请中，我们建议检查急性感染如何逆转 PDL-1 介导的 T 细胞抑制的机制基础，并在自身免疫性糖尿病小鼠模型中测试逆转 PDL-1 功能的后果。本申请的目标 1 将利用具有特定细胞因子或细胞因子受体个体或组合缺陷的小鼠，探索特定炎症细胞因子在重编程 PDL-1 功能中的作用。本申请的目标 2 将使用从 PDL-1 缺陷小鼠中分离的细胞来检查 PDL-1 作用的特定免疫细胞类型，以赋予 T 细胞刺激或抑制作用。最后，目标 3 中概述的实验将直接测试急性感染以及前两个目标中描述的特定细胞因子和免疫细胞的作用如何使用糖尿病易感性 NOD 小鼠逆转 PDL-1 介导的耐受性。这些实验的结果将为易感个体如何触发自身免疫提供机制解释，更重要的是阐明参与这一过程的特异性免疫细胞因子和细胞，从而为1型糖尿病提供更合理的预防和免疫治疗。