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.

项目总结 Foxp3+调节性T细胞(TR)对于建立和维持免疫耐受以及操纵 TR活性是治疗自身免疫性和炎症性疾病的一种有吸引力的新治疗策略。这个 T细胞受体的发育、动态平衡和功能依赖于细胞因子IL-2，而T细胞受体结构性地表达 高亲和力的IL-2受体，使他们能够竞争限制激活的CD4+T细胞产生的IL-2。AS 为了增加tr的丰度和功能来治疗自身免疫性疾病，我们开发了一种新的 IL-2具有高度的受体选择性，在体内有效地扩大受体，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，在老鼠和人类身上， IL-2Mutien治疗与高激活的TR子集的显著扩张有关，其特征是 通过表达与T细胞受体刺激相关的激活标志物。此外，扩展的树 高水平表达免疫抑制分子CTLA4，IL-2突变蛋白治疗抑制其激活 树突状细胞(DC)及其表面关键共刺激配体CD80和CD86的表达 完全激活效应器T细胞所必需的。基于这些结果，我们假设IL-2突变治疗 促进TR/DC相互作用，这导致IL-2和TCR信号的协同作用，从而推动细胞增殖 抑制DC功能，阻止DC的激活、分化和 自身反应性T细胞的功能。在这项提议中，我们使用了许多创新的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的理解 促进TR的扩张和免疫耐受的诱导。这对英译英具有重要的启示意义。 IL-2突变体进入治疗用途，将为IL-2介导的基础生物学提供重要的新见解 调节激素受体的动态平衡和功能。