Mechanisms of Il-2-mediated immune tolerance

项目摘要 Foxp 3+调节性T细胞（TR）对于建立和维持免疫耐受以及操纵免疫耐受是必不可少的。 TR活性是治疗自身免疫性和炎症性疾病的有吸引力的新治疗策略。的 TR的发育、稳态和功能依赖于细胞因子IL-2，TR组成性表达IL-2， 高亲和力IL-2受体，使它们能够竞争限制由活化的CD 4 + T细胞产生的IL-2。作为 一种增加TR丰度和功能以治疗自身免疫性疾病的策略，我们开发了一种新的 具有高度TR选择性的IL-2“突变蛋白”，在体内有效地扩展TR，并阻止正在进行的自身免疫和 在NOD小鼠中诱导持久的疾病保护。有趣的是，我们已经证明，在小鼠和人类中， IL-2多烯治疗与高度活化的TR亚群的显著扩增相关， 通过表达与T细胞受体刺激相关的活化标志物。此外，扩大TR 表达高水平的免疫抑制分子CTLA 4，IL-2突变蛋白处理抑制了活化 树突状细胞（DC）及其表面表达的关键共刺激配体CD 80和CD 86， 这是完全激活效应T细胞所必需的。基于这些结果，我们假设IL-2突变蛋白治疗 促进TR/DC相互作用，并且这导致协同的IL-2和TCR信号传导， 和高度活化的TR的扩增，其抑制DC功能并阻止DC的活化、分化和 自身反应性T细胞的功能。在这个提议中，我们使用了一些创新的方法来检验这一假设， 这些实验将提供一个全面的机制了解如何IL-2突变蛋白的功能， 促进TR扩增和诱导免疫耐受。这对翻译具有重要意义。 IL-2突变蛋白进入治疗用途，并将提供重要的新的见解，在基础生物学的IL-2介导的 TR稳态和功能的控制。

PROJECT SUMMARY Foxp3+ regulatory T cells (TR) are essential for establishing and maintaining immune tolerance, and manipulating TR activity is an attractive new therapeutic strategy for treating autoimmune and inflammatory diseases. The development, homeostasis and function of TR depends on the cytokine IL-2, and TR constitutively express the high affinity IL-2 receptor which allows them to compete for limiting IL-2 produced by activated CD4+ T cells. As a strategy for increasing TR abundance and function to treat autoimmune disease, we have developed a novel IL-2 ‘mutein’ that is highly TR selective, potently expands TR in vivo, and arrests ongoing autoimmunity and induces durable disease protection in NOD mice. Interestingly, we have shown that in both mice and humans, IL-2 mutien treatment is associated with pronounced expansion of a subset of highly activated TR characterized by expression of activation markers associated with T cell receptor stimulation. Furthermore, expanded TR express high levels of the immunosuppressive molecule CTLA4, and IL-2 mutein treatment inhibits the activation of dendritic cells (DCs) and their surface expression of the key co-stimulatory ligands CD80 and CD86 that are required for full effector T cell activation. Based on these results, we hypothesize that IL-2 mutein treatment promotes TR/DC interaction, and that this results in synergistic IL-2 and TCR signaling that drives the proliferation and expansion of highly activated TR that inhibit DC function and prevent the activation, differentiation and function of autoreactive T cells. In this proposal we use a number of innovative methods to test this hypothesis, and these experiments will provide a comprehensive mechanistic understanding of how IL-2 muteins function to promote TR expansion and induction of immune tolerance. This has important implications for the translation of IL-2 muteins into therapeutic use, and will provide important new insights in the basic biology of IL-2-mediated control of TR homeostasis and function.