Reprogramming of Regulatory T cells to Promote Immune Tolerance

调节性 T 细胞重编程以促进免疫耐受

基本信息

批准号：
10192652
负责人：
Louis-Marie Charbonnier
金额：
$ 44.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10192652
关键词：
Agreement Allergic Antigens Asthma Attenuated Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Cell Differentiation process Cell physiology Cells Cellular Metabolic Process Cellular biology Chronic Coupled Cues Development Disease Disease model Elements Environmental Exposure Epigenetic Process Equilibrium Evolution Exhibits FOXP1 gene FOXP3 gene Failure Female Food Gene Expression Profile Genes Genetic Transcription Glucose Heterogeneity Human IL2RA gene Immune Immune System Diseases Immune Tolerance Immune response Inflammation Inflammatory Interleukin-2 Intervention Lead Lymphoproliferative Disorders Maintenance Mendelian disorder Metabolic Molecular Mus Oxidative Phosphorylation Pathway interactions Peripheral Pharmacology Phenotype Play Population Precision therapeutics Process Proteins Regulation Regulatory T-Lymphocyte Role Severities Severity of illness Signal Transduction Time aerobic glycolysis airborne allergen base combinatorial commensal microbes cytokine effector T cell fatty acid oxidation genetic approach graft vs host disease human subject immunoregulation imprint improved inflammatory milieu insight loss of function mutation novel novel strategies novel therapeutics personalized intervention prevent programs respiratory restoration single-cell RNA sequencing targeted treatment transcription factor transcriptome

项目摘要

ABSTRACT Regulatory T (Treg) cells play a fundamental role in enforcing peripheral immunological tolerance to self-antigens, commensal flora, and innocuous foreign antigens. The transcription factor Foxp3 is indispensable to Treg cell differentiation and immunoregulatory functions. Loss of function mutations in Foxp3 precipitate a severe autoimmune inflammatory disorder, while acquired deficiency in chronic inflammatory and autoimmune conditions destabilizes Treg cells and sustains disease chronicity and severity. Foxp3-deficient Treg (∆Treg) cells lack suppressor function and manifest an effector T (Teff) cell–like phenotype. Nevertheless, they continue to a core regulatory transcriptome, indicating the potential to restore their regulatory function. In agreement with this hypothesis, we have recently demonstrated that Foxp3 deficiency dysregulates metabolic checkpoint mTORC2 signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in ∆Treg cells greatly ameliorated disease in Foxp3-deficient mice, improved ∆Treg cells suppressive capacities, and suppressed their Teff cell–like glycolytic and respiratory programs. These findings established for the first time the potential to reprogram ∆Treg cells in favor of enhanced tolerance, an approach applicable to both monogenic and common immune dysregulatory diseases. More recently, we have established that the ∆Treg cells are heterogenous, ranging along a spectrum from cells with high regulatory potential to ones more advanced towards a Teff cell-like phenotype. Based on these results, we postulate that Foxp3 deficiency destabilizes ∆Treg cells towards Teff cell-like programs in a step-wise process that can be reversed by precision interventions to re-establish their regulatory functions. Specifically, the degeneration of ∆Treg cells in to Teff-like cells involves the transition from a CD25+Foxp1high cell population into CD25–Foxp1low activated Teff-like cells that ultimately emerge as ex-Treg cells lacking in a Treg cell epigenetic imprint. The role of IL-2/CD25 and Foxp1 in this transition will be examined using functional and genetic approaches (Aim 1). Under Aim 2, we will examine the metabolic checkpoints involved in this transition and the capacity of targeted combinatorial metabolic and functional interventions to reprogram ∆Treg cells in favor of tolerance. Under Aim 3, we will employ insights gained from our preliminary and proposed studies to reinforce the regulatory functions of Foxp3-sufficient Treg cells in the context of autoimmune and inflammatory disease models. The proposed analysis of ∆Treg cell subsets and their modulation by single and combinatorial interventional strategies represents a novel approach to restoring immune tolerance in monogenic and common immune dysregulatory diseases, including autoimmune and allergic disorders and graft versus host disease.

抽象的调节性 T (Treg) 细胞在增强外周免疫耐受自身抗原方面发挥着重要作用，共生菌群和无害的外来抗原转录因子 Foxp3 对于 Treg 细胞是不可或缺的。 Foxp3 的功能突变导致分化和免疫调节功能丧失。自身免疫性炎症性疾病，同时获得性慢性炎症和自身免疫性缺陷条件会破坏 Treg 细胞的稳定性并维持 Foxp3 缺陷 Treg (ΔTreg) 细胞的疾病慢性化和严重程度。缺乏抑制功能并表现出效应 T (Teff) 细胞样表型。核心调节转录组，表明恢复其调节功能的潜力与此一致。假设，我们最近证明 Foxp3 缺陷会导致代谢检查点 mTORC2 失调信号传导并引起有氧糖酵解和氧化磷酸化的增强。 ΔTreg细胞中的mTORC2接头基因Rictor极大地改善了Foxp3缺陷小鼠的疾病，改善了ΔTreg 细胞抑制能力，并抑制其 Teff 细胞样糖酵解和呼吸程序。研究结果首次证实了重新编程 ΔTreg 细胞有利于增强耐受性的潜力，最近，我们有了适用于单基因和常见免疫失调疾病的方法。确定 ΔTreg 细胞是异质的，范围涵盖具有高度调节性的细胞具有更先进的 Teff 细胞样表型的潜力。基于这些结果，我们假设 Foxp3 缺陷会破坏 ΔTreg 细胞向 Teff 细胞样程序的稳定性这是一个逐步的过程，可以通过精确干预来逆转，以重建其监管功能。具体来说，ΔTreg 细胞向 Teff 样细胞的退化涉及从 CD25+Foxp1high 细胞的转变群体进入 CD25–Foxp1low 激活的 Teff 样细胞，最终作为缺乏 Treg 细胞的前 Treg 细胞出现 IL-2/CD25 和 Foxp1 在这一转变中的作用将使用功能和遗传方法（目标 1）在目标 2 下，我们将检查参与这一转变的代谢检查点。以及有针对性的组合代谢和功能干预措施对 ΔTreg 细胞进行重新编程以利于其的能力在目标 3 下，我们将利用从我们的初步研究和拟议研究中获得的见解来加强。 Foxp3 充足的 Treg 细胞在自身免疫和炎症性疾病中的调节功能模型对 ΔTreg 细胞亚群及其调节的建议分析。干预策略代表了一种恢复单基因和常见免疫耐受的新方法免疫失调疾病，包括自身免疫性疾病和过敏性疾病以及移植物抗宿主病。