Inflammatory cascades disrupt Treg function through epigenetic mechanisms

炎症级联反应通过表观遗传机制破坏 Treg 功能

• 批准号: 10555213
• 负责人: William A Faubion
• 金额: $ 49.85万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555213
• 关键词: 3-Dimensional; Adoptive Cell Transfers; Adoptive Transfer; Anti-Inflammatory Agents; Architecture; Articulation; Automobile Driving; Binding; Bioinformatics; Biology; CCCTC-binding factor; CD4 Positive T Lymphocytes; Cell Therapy; Cell physiology; Cells; Chromatin; Chromatin Loop; Chromatin Structure; Chronic; Clinic; Complex; Crohn' s disease; DNA; Derivation procedure; Dermatologic; Development; Disease; Drug Targeting; ETS Family Protein; Enhancers; Environment; Epigenetic Process; Evaluation; Event; Exposure to; FOXP3 gene; Genes; Genetic Transcription; Goals; Grant; Human; Human Biology; Human Engineering; Immune; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Investigational Therapies; Kinetics; Lesion; Lymphocyte; Maintenance; Malignant Neoplasms; Mediating; Mus; Neurologic; Pathogenicity; Pathway interactions; Patients; Peripheral; Phenocopy; Phenotype; Polycomb; Proteins; Public Health; Publishing; Qualifying; Regulatory T-Lymphocyte; Repression; Repressor Proteins; Research; Risk; Role; Shapes; Signal Transduction; Spleen; Spontaneous colitis; T-Lymphocyte; Testing; Therapeutic; Therapy trial; Work; cellular engineering; cytokine; epigenetic drug; epigenetic therapy; epigenome; epigenomics; experience; gene network; gene repression; gut inflammation; in vivo; inflammatory milieu; insight; laboratory development; novel; programs; promoter; prototype; therapeutic evaluation; therapeutic target

PROJECT SUMMARY/ABSTRACT CD4+FOXP3+lymphocytes are expanded within the intestinal inflammatory lesion of Crohn’s disease (CD); however, ongoing inflammation belies presumed anti-inflammatory function of this cell. FOXP3 is required for differentiation and function of T regulatory (TREG) cells. FOXP3-mediated gene repression is lost in intestinal T cells of CD patients. Indeed, “FOXP3+ Crohn’s cell (FOXP3+CD)” bears a transcriptional signal more closely related to the pro-inflammatory TH17 cell. Derivation, function, and therapeutic implications of the FOXP3+CD cell remain poorly understood. Our long-term goal is to dissect epigenetic mechanisms regulating TREG cellular differentiation and function in the setting of GI inflammation. Consequently, the objective is to identify mechanisms responsible for activation of the TH17 phenotypic transcriptional network within intestinal FOXP3+CD cells and test therapeutic opportunities to restore their regulatory function in vivo. Our central hypothesis is that a shared chromatin configuration between TREG and TH17 cells allows for rapid activation of a TH17-like pro-inflammatory gene program in intestinal FOXP3+TREG cells. A set of TH17-relevant genes are accessible, yet not active in human TREG cells. A defining feature of the TH17 program was significant enrichment of CCCTC binding factor (CTCF) motifs. CTCF, a well-known topologically-associated domain (TAD) insulator protein, also mediates intra-TAD chromosomal looping and enhancer-promoter interaction regulating gene transcription. Bioinformatic analysis of this TH17 program indicates an inhibitory role for Polycomb Repressor Complex 1 (PRC1). Deletion of PRC1 in murine FOXP3+ cells led to secretion of prototypic TH17-like cytokines in FOXP3+ cells, and spontaneous colitis. The rationale is that with mechanistic insight into the biology of intestinal TREG cell in inflammation, one can apply targeted FOXP3+ CD cell-directed therapy including engineering of human TREG cells for adoptive cell therapy trials. To test the central hypothesis and obtain the overall objective we will address the following three questions: Aim1: Why are CTCF motifs associated with the TH17 program? Aim2: Why are TH17-associated genes accessible yet not active in TREG cells? Aim3: Why do FOXP3+CD cells express prototypic TH17 cytokines? Upon conclusion, we will understand the epigenetic pathways and 3D chromatin architecture spawning the FOXP3+CD cell and mechanisms shaping their development and function. This contribution is significant as the FOXP3+CD cell is expanded in the Crohn’s lesion, phenocopies TH17 cell which is implicated in Crohn’s disease (and other inflammatory diseases), and represents an important epigenetic drug target for systemic or re-engineered cellular therapy. There is general acknowledgement of risk of FOXP3+ TREG cells converting to pathogenic FOXP3+TH17-like cells upon adoptive transfer in Crohn’s trials; yet, this project is the first to articulate both signature and precise epigenetic events that regulate activation of the TH17 program in TREG cells.

项目摘要/摘要 CD4+FOXP3+淋巴细胞在克罗恩病的肠道炎症病变内扩张（CD）； 然而，持续的炎症掩盖了该细胞的抗炎功能。 FOXP3是必需的 T调节（TREG）细胞的分化和功能。 FOXP3介导的基因表达在肠道中丢失 CD患者的T细胞。确实，“ Foxp3+ Crohn的单元格（FOXP3+ CD）”带有转录信号 促炎性Th17细胞的推导，功能和治疗意义。 FOXP3+CD细胞仍然了解不足。我们的长期目标是剖析调节的表观遗传机制 Treg细胞分化和在GI炎症的情况下的功能。因此，目标是 确定负责激活Th17表型转录网络的机制 FOXP3+CD细胞和测试疗法的机会，可以在体内恢复其调节功能。我们的中心 假设是Treg和Th17细胞之间的共享染色质构型允许快速激活 肠道Foxp3+Treg细胞中的Th17样促炎基因程序。一组与Th17相关的基因 可访问，但在人treg细胞中不活跃。 TH17程序的定义功能很重要 CCCTC结合因子（CTCF）基序的富集。 CTCF，众所周知的拓扑相关域 （TAD）绝缘子蛋白，还介导了TAD内染色体环和增强子促销的相互作用 调节基因转录。该TH17计划的生物信息学分析表明对 Polycomb抑制剂复合物1（PRC1）。在鼠类Foxp3+细胞中删除Prc1导致分泌 Foxp3+细胞中的原型Th17样细胞因子和赞助结肠炎。理由是机械 深入了解肠道肠道细胞的生物学，可以应用针对的FOXP3+ CD细胞定向 治疗，包括用于自适应细胞治疗试验的人treg细胞的工程。测试中央 假设并获得总体目标，我们将解决以下三个问题：AIM1：为什么CTCF是 与TH17程序相关的主题？ AIM2：为什么Th17相关基因可访问但不活跃 treg细胞？ AIM3：为什么FOXP3+CD细胞表达原型Th17细胞因子？总结一下，我们将 了解表观遗传途径和3D染色质体系结构产生Foxp3+CD细胞和 塑造其发展和功能的机制。此贡献很重要，因为Foxp3+CD单元格是 在克罗恩病的病变中扩展，表型Th17细胞在克罗恩病（以及其他 炎症性疾病），代表了全身或重新设计的重要表观遗传药物靶标 细胞疗法。人们普遍承认Foxp3+ Treg细胞转化为致病性的风险 在克罗恩（Crohn）试验中自适应转移后的Foxp3+Th17样细胞；但是，这个项目是第一个阐明两者的项目 调节Treg细胞中Th17程序激活的签名和精确的表观遗传事件。