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.

项目概要 Foxp3+ 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至关重要。 TR 活性是治疗自身免疫性疾病和炎症性疾病的一种有吸引力的新治疗策略。 TR 的发育、稳态和功能取决于细胞因子 IL-2，TR 组成型表达 高亲和力 IL-2 受体，使它们能够竞争限制激活的 CD4+ T 细胞产生的 IL-2。 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 IL-2“突变蛋白”具有高度 TR 选择性，可能在体内扩大 TR，并阻止持续的自身免疫和 在 NOD 小鼠中诱导持久的疾病保护是有意义的，我们已经证明在小鼠和人类中， IL-2突变治疗与高度激活的TR子集的显着扩张相关 通过与 T 细胞受体刺激相关的激活标记物的表达，进一步扩大 TR。 表达高水平的免疫抑制分子 CTLA4，IL-2 突变蛋白治疗可抑制其激活 树突状细胞 (DC) 及其关键共刺激配体 CD80 和 CD86 的表面表达 完全效应 T 细胞激活所需的基于这些结果，我们追踪了 IL-2 突变蛋白治疗。 促进 TR/DC 相互作用，从而产生协同的 IL-2 和 TCR 信号，从而驱动增殖 和高度激活的 TR 的扩展，抑制 DC 功能并阻止激活、分化和 自身反应性 T 细胞的功能 在本提案中，我们使用了多种创新方法来检验这一假设， 这些实验将提供对 IL-2 突变蛋白如何发挥作用的全面机制理解 促进TR扩增和诱导免疫耐受，这对于翻译具有重要意义。 IL-2 突变蛋白进入治疗用途，并将为 IL-2 介导的基础生物学提供重要的新见解 TR 稳态和功能的控制。