Robust immune tolerance conferred by Foxp3 transcriptional regulation

Foxp3 转录调控赋予强大的免疫耐受性

基本信息

批准号：
10541899
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
项目类别：
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/10541899
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 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 deprivation early onset epigenetic regulation experimental study genetic element immune activation immunological status improved insight mouse genetics neonate novel pharmacologic postnatal promoter single-cell RNA sequencing tool

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 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 deprivation early onset epigenetic regulation experimental study genetic element immune activation immunological status improved insight mouse genetics neonate novel pharmacologic postnatal promoter single-cell RNA sequencing tool

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项目摘要

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转录法规赋予的强大免疫耐受性调节t（treg）细胞积极抑制引起多种自身免疫性的自我毁灭性T细胞疾病。尽管取得了重大进展，但基于TREG的治疗受到有限的方法的显着限制提高Treg抑制能力。我们旨在剖析Treg诱导和血统的机械过程维护以发现赋予可靠免疫抑制功能的因素和机制。 Treg细胞由传递到分化的T细胞的环境提示的收敛性引起的变化，导致随机的Treg发育。此外，遗传元素的DNA序列在个体中调节Treg谱系身份也有所不同。鉴于巨大的T细胞抗原受体（TCR）和目标特异性，Treg细胞被许多不确定性诱导。一旦投入，Treg 通过细胞中的和 - 超级因素，维持命运以扩展抑制功能，这些因素不断波动。所有这些不确定性提出了一个问题，即Treg细胞如何赋予耐受性耐受性。 Treg Master调节剂Foxp3的研究提供了一种独特的方法来解决此问题，因为Foxp3 表达中心Treg命运确定和功能。我们假设有足够的缓冲能力有效的Treg发育和谱系稳定性赋予了遗传变异和免疫扰动。为了检验这一假设，我们检查了指示Treg诱导和血统的FOXP3增强子稳定。众所周知，单个FOXP3增强剂在FOXP3感应或维护中扮演特定于阶段的角色。然而，尽管有明显的免疫失调，但带有个体突变的小鼠会出现轻度 Treg发育或谱系稳定性的缺陷。为了解决这个谜，我们检查了表观遗传机制介导FOXP3表达并假设FOXP3增强子协调以实现有效的Treg感应或稳定的谱系身份，以实现足够的Treg缓冲能力。我们产生了新的鼠标菌株来检验我们的假设，发现两个相互作用的Foxp3的删除增强子引起致命的自身免疫性疾病，并伴有严重的Treg诱导或谱系缺陷稳定。该结果与其他研究一起描述了获得的全部Treg缓冲能力通过协调FOXP3增强器。在拟议的研究中，我们将完全发现免疫学小鼠严重降低了Treg诱导或谱系稳定性的后果。我们将开发新算法并使用单细胞RNA测序来评估Treg库的多样性和谱系稳定性来推断Treg Buffering 容量。我们还将使用新开发的鼠标遗传工具来确定连续胸腺的作用 Treg诱导保持Treg缓冲能力。总体而言，我们的研究将揭示由Foxp3赋予的全部Treg抑制能力转录调节。它将改善我们对Treg相关自身免疫性疾病的基本理解。