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

描述(由申请人提供)： 哺乳动物免疫系统包含多个错综复杂的相反刺激和抑制信号调节网络，这些网络共同允许在感染期间迅速动员保护性病原体特异性免疫，同时抑制可导致自身免疫的自我反应性免疫反应。有趣的是，虽然组成这些免疫刺激或抑制网络的分子现在已经被确定，但器官特异性自身免疫性疾病如何和为什么发生的生物学基础，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，在很大程度上仍不清楚。在I型糖尿病的非肥胖糖尿病(NOD)模型中，阻止胰岛细胞减少的免疫耐受在很大程度上是通过编程细胞死亡配体-1(PDL-1)来调节T细胞抑制的。在许多慢性感染模型中，PDL-1标记的抑制维持T细胞的耗竭。然而，与之形成鲜明对比的是，我们最近对原发单核细胞增多性李斯特菌感染的研究表明，在急性感染条件下，这些由PDL-1介导的抑制信号被重新编程为T细胞刺激信号。这些结果结合流行病学观察，即大多数1型糖尿病患者是由非特异性传染病引发的，表明通过重新编程PDL-1对自身抗原的正常抑制作用，急性感染可能 引发自身免疫性糖尿病。因此，在这项应用中，我们建议研究急性感染如何逆转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。本申请的目的1将探索特定炎性细胞因子在特定细胞因子或细胞因子受体单个或联合缺陷小鼠重新编程PDL-1功能中的作用。这项应用的目的2将利用从PDL-1缺陷小鼠分离的细胞来检测PDL-1作用于的特定免疫细胞类型(S)，以赋予T细胞刺激或抑制效应。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逆转糖尿病易感NOD小鼠的PDL-1介导的耐受。这些实验的结果将为易感个体如何触发自身免疫提供一个机制解释，更重要的是阐明参与这一过程的特定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。

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.