Mechanisms of Il-2-mediated immune tolerance

IL-2介导的免疫耐受机制

• 批准号: 10608299
• 负责人: Daniel J Campbell
• 金额: $ 26万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-18 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608299
• 关键词: Affinity; Antigen Presentation; Autoimmune Diseases; Autoimmunity; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD80 gene; CD86 gene; CTLA4 gene; Cell Communication; Cell physiology; Cellular Metabolic Process; Dendritic Cells; Dendritic cell activation; Development; Disease; FOXP3 gene; Funding Mechanisms; Homeostasis; Human; Immune Tolerance; Inbred NOD Mice; Inflammatory; Interleukin 2 Receptor; Interleukin-2; Ligands; Measures; Mediating; Metabolic; Methods; Mus; Pre-Clinical Model; Proliferating; Regulation; Regulatory T-Lymphocyte; Research; Signal Transduction; Surface; T cell response; T-Cell Activation; T-Cell Receptor; Techniques; Testing; Therapeutic; Therapeutic Uses; Translations; autoreactive T cell; cytokine; early phase clinical trial; effector T cell; experimental study; in vivo; innovation; insight; mouse model; mutein 2; novel; novel therapeutic intervention; prevent

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.

项目摘要 FOXP3+调节性T细胞（TR）对于建立和维持免疫耐受性和操纵至关重要 TR活动是一种用于治疗自身免疫性和炎症性疾病的有吸引力的新治疗策略。这 TR的发育，稳态和功能取决于细胞因子IL-2，而TR则表达 高亲和力IL-2受体，使他们能够竞争激活的CD4+ T细胞产生的IL-2。作为 提高TR抽象和功能治疗自身免疫性疾病的策略，我们已经开发了一种新颖的 IL-2高度选择性，可能会在体内扩展TR，并逮捕正在进行的自身免疫性和 在NOD小鼠中诱导持久的疾病保护。有趣的是，我们已经表明，在老鼠和人类中， IL-2 Mutien处理与高度激活Tr的一子集的明显扩展有关 通过表达与T细胞受体刺激相关的激活标记。此外，扩展的tr 表达高水平的免疫抑制分子CTLA4和IL-2静脉素处理抑制激活 树突状细胞（DC）及其表面表达的关键共刺激配体CD80和CD86是 完全效应T细胞激活所必需的。基于这些结果，我们假设IL-2静脉素治疗 促进TR/DC相互作用，这导致协同IL-2和TCR信号传导驱动增殖 并扩展高度激活的TR，该TR抑制直流功能并防止激活，分化和 自动反应性T细胞的功能。在此提案中，我们使用许多创新方法来检验这一假设， 这些实验将对IL-2静脉素蛋白如何发挥作用，提供全面的机械理解 促进TR扩展和诱导免疫耐受性。这对翻译具有重要意义 IL-2静脉毒素用于治疗用途，并将在IL-2介导的基本生物学中提供重要的新见解 控制TR稳态和功能。