Robust immune tolerance conferred by Foxp3 transcriptional regulation

Foxp3 转录调控赋予强大的免疫耐受性

• 批准号: 10330039
• 负责人: Yongqiang Feng
• 金额: $ 44.88万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-20 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330039
• 关键词: Address; Adult; Affect; Algorithms; Antigen Targeting; Autoimmune Diseases; Autoimmunity; Biology; Buffers; Bypass; Cell Count; Cell physiology; Cues; DNA Sequence; Defect; Development; Enhancers; Epigenetic Process; FOXP3 gene; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Goals; Immune; Immune Tolerance; Immunologics; Immunosuppression; Impairment; Incidence; Individual; Interleukin-2; Investigation; Life; Literature; Longevity; Maintenance; Measures; Mediating; Methods; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Nature; Neonatal; Nuclear Protein; Operative Surgical Procedures; Outcome; Output; Pharmacology; Play; Process; Regulation; Regulatory Element; Regulatory T-Lymphocyte; Reporting; Role; Severities; Specificity; T cell differentiation; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Techniques; Testing; Thymectomy; Thymus Gland; Transcription Process; Transcriptional Regulation; Uncertainty; Variant; anti-tumor immune response; base; deprivation; early onset; epigenetic regulation; experimental study; genetic element; immune activation; immunological status; improved; insight; mouse genetics; neonate; novel; postnatal; promoter; single-cell RNA sequencing; tool

Robust immune tolerance conferred by Foxp3 transcriptional regulation Regulatory T (Treg) cells actively suppress self-destructive T cells that cause a variety of autoimmune diseases. Despite significant progress, Treg-based treatment is significantly constrained by limited methods to improve Treg suppressive capacity. We aim to dissect the mechanistic processes of Treg induction and lineage maintenance to uncover the factors and mechanisms conferring robust immune suppressive function. Treg cells are induced by the convergence of environmental cues delivered to differentiating T cells with considerable variations, resulting in stochastic Treg development. Besides, the DNA sequences of the genetic elements regulating Treg lineage identity also vary among individuals. Given the enormously diverse T cell antigen receptors (TCRs) and target specificities, Treg cells are induced with many uncertainties. Once committed, Treg fate is maintained for extended suppressive function by cell-intrinsic and -extrinsic factors that constantly fluctuate. All these uncertainties raise a question about how robust immune tolerance is conferred by Treg cells. Study of Treg master regulator Foxp3 offers a unique approach to address this question, because Foxp3 expression centers Treg fate determination and function. We hypothesize that an adequate buffering capacity conferred by efficient Treg development and lineage stability opposes the genetic variations and immune perturbations. To test this hypothesis, we examined the Foxp3 enhancers that dictate Treg induction and lineage stability. Individual Foxp3 enhancers were known to play stage-specific roles in Foxp3 induction or maintenance. However, mice bearing their individual mutations develop mild if any immune dysregulation despite significant defects in Treg development or lineage stability. To solve this mystery, we examined the epigenetic mechanisms mediating Foxp3 expression and hypothesize that Foxp3 enhancers coordinate to enable efficient Treg induction or stable lineage identity for adequate Treg buffering capacity. We generated new mouse strains to test our hypotheses and found that deletion of two interacting Foxp3 enhancers caused fatal autoimmune diseases accompanied with severe defects of Treg induction or lineage stability. This result together with other studies delineates a full spectrum of Treg buffering capacity acquired through coordinating Foxp3 enhancers. In the proposed study, we will fully uncover the immunological consequences of mice with severely reduced Treg induction or lineage stability. We will develop new algorithms and use single cell RNA sequencing to assess Treg repertoire diversity and lineage stability to infer Treg buffering capacity. We will also use our newly developed mouse genetic tools to determine the role of continuous thymic Treg induction in maintaining the Treg buffering capacity. Overall, our study will uncover a full spectrum of Treg suppressive capacity conferred by Foxp3 transcriptional regulation. It will improve our basic understanding of Treg-related autoimmune diseases.

Foxp3转录调控赋予的强大免疫耐受性 调节性T（Treg）细胞积极抑制自我破坏性T细胞，导致各种自身免疫性疾病。 疾病尽管取得了重大进展，但基于Treg的治疗受到有限方法的显著限制， 提高Treg抑制能力。我们的目标是剖析Treg诱导和谱系的机制过程， 维持，以揭示赋予强大的免疫抑制功能的因素和机制。Treg细胞 是由传递给分化中的T细胞的环境信号的会聚引起的， 变异，导致随机Treg发育。此外，遗传元件的DNA序列 调节Treg谱系身份的个体也各不相同。鉴于T细胞抗原的多样性 由于受体（TCR）和靶特异性，Treg细胞的诱导具有许多不确定性。一旦被抓，崔格 命运是由细胞内源性和外源性因素维持的， 波动所有这些不确定性都提出了一个问题，即Treg细胞赋予免疫耐受性的强度如何。 Treg主调节因子Foxp3的研究为解决这一问题提供了一种独特的方法，因为Foxp3 表达中心Treg命运决定和功能。我们假设，足够的缓冲能力 由有效Treg发育和谱系稳定性赋予的免疫调节功能对抗遗传变异和免疫调节功能。 扰动为了验证这一假设，我们检测了Foxp3增强子，其决定了Treg的诱导和谱系， 稳定已知单个Foxp3增强子在Foxp3诱导或维持中发挥阶段特异性作用。 然而，携带它们的个体突变的小鼠即使有显著的免疫失调，也会出现轻微的免疫失调。 Treg发育或谱系稳定性的缺陷。为了解开这个谜团，我们研究了 介导Foxp3表达，并假设Foxp3增强子协调以实现有效的Treg诱导 或稳定的谱系身份，以获得足够的Treg缓冲能力。 我们产生了新的小鼠品系来测试我们的假设，发现缺失两个相互作用的Foxp3 增强子导致致命的自身免疫性疾病，并伴有Treg诱导或谱系的严重缺陷 稳定该结果与其他研究一起描绘了获得的Treg缓冲能力的全谱 通过协调Foxp3增强子。在拟议的研究中，我们将充分揭示免疫学 Treg诱导或谱系稳定性严重降低的小鼠的后果。我们将开发新的算法 并使用单细胞RNA测序来评估Treg库多样性和谱系稳定性，以推断Treg缓冲 容量我们还将使用我们新开发的小鼠遗传工具来确定连续胸腺细胞的作用。 Treg诱导维持Treg缓冲能力。 总的来说，我们的研究将揭示Foxp3赋予Treg抑制能力的全谱。 转录调控这将提高我们对Treg相关自身免疫性疾病的基本认识。