Apoptotic cells induce tolerance through TRAIL-expressing CD8+ regulatory T cells

宿主对致病性损伤的反应涉及复杂的炎症反应和细胞免疫反应， 因此，产生保护性免疫或耐受的决定通常取决于T细胞首先 遇到抗原（Ag）。虽然免疫耐受的诱导在近100年前首次被描述， 直到20世纪70年代才提出耐受性可以由T细胞主动介导并转移到幼稚受体。 调节性T细胞（Treg）是免疫耐受的关键介质，了解其调控机制是免疫耐受的关键。 产生和功能对T细胞介导的自身免疫性疾病的治疗方法的发展有着巨大的影响 和慢性移植排斥在过去的几年里，人们对T细胞介导的免疫调节重新产生了兴趣。 十年来，绝大多数研究主要集中在CD 4 + Treg上。然而，早期的报告详细说明了免疫 耐受性描述了CD 8 + Treg的活性，关于CD 8 + Treg如何发育和 功能对T细胞耐受性的研究表明，将Ag注射到眼前房（AC）中可诱导T细胞耐受性。 免疫偏离（称为前房相关免疫偏离，ACAID）-其特征在于诱导免疫偏离， 抗体应答，同时伴有细胞介导的免疫功能受损（或耐受）。ACAID的另一个关键特性是， 这种耐受性是“传染性的”，即它可以从耐受个体转移到未受感染的受体。在许多方面 通过眼睛AC呈递的对Ag的免疫应答与静脉内注射后诱导的应答非常相似。 （静脉注射）可溶性Ag免疫：攻击后的免疫耐受性，将耐受性转移至未处理动物的能力 用从耐受小鼠获得的CD 8 + T细胞，Ag偶联细胞的凋亡死亡诱导耐受的必要性， 并且，根据我们发表的和初步的数据，TNF相关的凋亡诱导配体（TRAIL）在肿瘤坏死因子相关的免疫反应中的关键作用。 建立宽容。 在这两个模型系统中观察到的公差不仅仅是由于未能预充，而是由于 产生CD 8 + Treg。为了进一步研究在这两种模型中诱导的耐受性的假设， 通过表达TRAIL的CD 8 + Treg介导，我们提出了以下具体目的：目的1 -确定 抗原特异性T细胞的外周缺失对表达TRAIL的CD 8 + Treg诱导耐受性的影响，Aim 2 - 确定活化凋亡细胞与未处理细胞相比不能诱导耐受的机制 目的3 -确定TRAIL在抗原结合能力中的作用， 通过AC施用所述抗体以刺激介导全身耐受性的抗原特异性调节性CD 8 + Treg。作为 自从TRAIL作为一种杀肿瘤分子被首次发现以来，人们对它的兴趣已经增长，现在已知TRAIL具有 超越肿瘤监测的领域还重新对T细胞介导的抑制产生了兴趣， 新试剂和新技术的可用性。因此，我们的计划将研究表达TRAIL的CD 8 + Treg在肿瘤发生中的作用。 使用2种经典耐受模型诱导和维持免疫耐受，目的是 将我们的发现应用于自身免疫治疗或提高移植存活率。

The host response to pathogenic insults involves complex inflammatory responses and cellular immune reactions, such that the decision to generate protective immunity or tolerance often depends on the context in which T cells first encounter antigen (Ag). While the induction of immunological tolerance was first described almost 100 years ago, the idea that tolerance could be actively mediated by T cells and transferred to na¿ve recipients was not proposed until the 1970's. Regulatory T cells (Treg) are critical mediators of immune tolerance, and understanding the mechanisms that govern their generation and function has enormous bearing on the development of therapies for T cell-mediated autoimmune diseases and chronic transplant rejection. There has been a renewed interest in T cell-mediated immune regulation over the last decade, with the vast majority of research focused primarily on CD4+ Treg. However, the early reports detailing immune tolerance described the activity of CD8+ Treg, and there is still very little known regarding how CD8+ Treg develop and function. Studies on T cell tolerance have shown that Ag injection into the anterior chamber (AC) of the eye induces an immune deviation (called anterior chamber associated immune deviation, ACAID) - characterized by the induction of an Ab response, with simultaneous impairment (or tolerance) of cell-mediated immunity. Another key feature of ACAID is that the tolerance is "infectious", i.e. it can be transferred from a tolerant individual to a na¿ve recipient. In many ways, the immunological response to Ag presented via the AC of the eye is very similar to the response induced after intravenous (i.v.) immunization of soluble Ag: immunological tolerance upon challenge, ability to transfer tolerance to na¿ve animals with CD8+ T cells obtained from tolerized mice, necessity for the apoptotic death of Ag-coupled cells to induce tolerance, and, based on our published and preliminary data, the key role of TNF-related apoptosis-inducing ligand (TRAIL) in the establishment of tolerance. The tolerance observed in both of these model systems is not simply due to the failure to prime, but results from the generation of CD8+ Treg. To further investigate the hypothesis that the tolerance induced in both of these models is mediated by TRAIL-expressing CD8+ Treg, we propose the following Specific Aims: Aim 1 - Determine the impact of peripheral deletion of antigen-specific T cells on the induction of tolerance by TRAIL-expressing CD8+ Treg, Aim 2 - Determine the mechanism behind the inability of activated apoptotic cells to induce tolerance, compared to na¿ve apoptotic cells, when injected intravenously, and Aim 3 - Determine the role of TRAIL in the ability of antigen administered through the AC to stimulate antigen-specific regulatory CD8+ Treg that mediate systemic tolerance. As interest in TRAIL has grown since its initial discovery as a tumoricidal molecule, TRAIL is now known to possess functions that go beyond tumor surveillance. There has also been a renewed interest in T cell-mediated suppression with the availability of new reagents and technology. Thus, our proposal will investigate the role of TRAIL-expressing CD8+ Treg in the induction and maintenance of immunological tolerance using 2 classical tolerance models, with the intention of applying our findings in the treatment of autoimmunity or increase transplant survival.