Transcriptional Regulation of Innate-Like T Cells

先天样 T 细胞的转录调控

• 批准号: 10441712
• 负责人: ALBERT S. BENDELAC
• 金额: $ 53.32万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441712
• 关键词: ATAC-seq; Address; Allergic; Antigens; Autoimmune Diseases; Autoimmunity; Bioinformatics; Bone Marrow; CRISPR/Cas technology; Cells; Characteristics; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Enhancers; Epigenetic Process; Exposure to; Flow Cytometry; GATA3 gene; Gene Expression; Generations; Genetic; Genetic Models; Goals; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Hypersensitivity; Immune response; Infection; Instruction; Liver; Lymphocyte; Lymphoid; Maps; Modeling; Mus; Natural Killer Cells; Nature; Pathway interactions; Pattern; Phase; Population; Property; Reporter; Reporting; Research; Resolution; Role; Salivary Glands; Special Population; Specificity; System; T-Lymphocyte; Th2 Cells; Thymus Gland; Tissues; Transcriptional Regulation; Uterus; Virus Diseases; ZNF145 gene; allergic airway inflammation; base; cytokine; design; epigenetic marker; genome-wide; in vivo; insight; microbial; mouse model; mutant; novel; novel strategies; pathogen; programs; response; tool; transcription factor; transcriptome sequencing; tumor

Innate lymphocytes include ILCs and innate-like NKT/MAIT/gamma-delta T lymphocytes that characteristically acquire Th1-, Th2- or Th17-like helper programs as well as tissue-resident properties during development in the bone marrow or thymus. In that respect, they differ fundamentally from their adaptive T cell counterparts, which are born naïve and recirculating, and only acquire tissue resident effector properties after exposure to pathogens and cytokines. Our research focuses on understanding the different mechanisms that control the parallel development of these populations in very different contexts. While we previously reported that the transcription factor (TF) PLZF was a common signature of innate lineages that directed their innate developmental fate, this project focuses on the layer of regulatory enhancers that differentially control the helper lineage-specific TFs Gata-3, T-bet and RORgt in innate and in adaptive lymphocytes, with emphasis on NK cells. We develop an epigenetic approach that identifies these enhancers and we generate enhancer reporter strains that are used to specifically manipulate innate and adaptive populations. The advantage of this approach is that epigenetic markers appear earlier and are more stable than the TF that they regulate. They also provide more complexity and specificity to dissect these developmental programs. In support of this approach, we recently identified a dedicated, ILC2- specific enhancer and generated mice lacking this enhancer to dissect the respective contribution of innate and adaptive type 2 responses in models of allergic airway inflammation. Here, we will apply this new approach to elucidate the issues of identity and relationship between NK cells and other group I lymphocytes, which express closely related properties and a degree of plasticity that have greatly confounded prior studies. The specific aims will (SA#1) identify candidate enhancers of the NK developmental pathway through a genome-wide bioinformatic search; (SA#2) validate these enhancers in vivo through CRISPR deletions; (SA#3) generate enhancer-reporter strains that specifically identify and manipulate NK cells. These studies will provide novel insights into the complexity and specificity of Group 1 Innate Lymphocytes, and generate new tools to probe their respective contributions in homeostasis and in tumor, infection and autoimmune conditions. RELEVANCE (See instructions): Our studies investigate a recently uncovered population of so-called innate lymphocytes. These cells act early in the immune response and provide major contributions in maintaining tissue health and in regulating the response in tumors, infections, allergy and autoimmune conditions. Specifically, we develop new genetic mouse models that will help define the differences between NK cells and ILC1s, two related subtypes that exert potent but distinct contributions against tumors and viral infections in mouse and human.

先天淋巴细胞包括ILC和先天类NKT/MAIT/γ-Delta T淋巴细胞，它们 特征性地获取Th1、Th2或Th17类辅助程序以及组织驻留属性 在骨髓或胸腺发育过程中。在这方面，它们从根本上不同于 适应性T细胞对应物，出生时天真，循环，只获得驻留的组织 暴露于病原体和细胞因子后的效应器特性。我们的研究重点是了解 在非常不同的背景下控制这些人口的并行发展的不同机制。 虽然我们之前报道过转录因子(Tf)PLZF是先天的常见签名 血统决定了他们与生俱来的发展命运，这个项目专注于监管层面 不同地控制先天和后天中辅助血统特定的TF GATA-3、T-bet和RORgt的增强子 在适应性淋巴细胞中，重点是NK细胞。我们开发了一种表观遗传学方法来识别 这些增强子和我们产生的增强子报告菌株被用来专门操纵先天 和适应能力强的种群。这种方法的优点是表观遗传标记出现得更早， 比他们监管的转运蛋白更稳定。它们还提供了更多的复杂性和特殊性来进行剖析 这些发展项目。为了支持这一方法，我们最近确定了一个专门的ILC2- 特异性增强子和缺乏该增强子的产生的小鼠分别剖析先天的贡献 过敏性呼吸道炎症模型中的适应性2型反应。在这里，我们将应用这一新的 阐明NK细胞与其他I组细胞的身份和关系问题的途径 淋巴细胞，它表达了密切相关的特性和一定程度的可塑性，这些特性和可塑性 混淆了之前的研究。具体目标将(SA#1)确定NK的候选增强剂 通过全基因组生物信息学搜索的发育途径；(SA#2)验证这些增强剂 体内通过CRISPR缺失；(SA#3)产生增强子报告菌株，专门识别和 操纵NK细胞。这些研究将为第一组的复杂性和特殊性提供新的见解 与生俱来的淋巴细胞，并产生新的工具来探索它们在动态平衡和... 肿瘤、感染和自身免疫状况。 相关性(请参阅说明)： 我们的研究调查了最近发现的所谓先天淋巴细胞的群体。这些细胞发挥作用 在免疫反应的早期，并在维持组织健康和调节方面做出重大贡献 在肿瘤、感染、过敏和自身免疫条件下的反应。具体地说，我们开发了新的 有助于确定NK细胞和ILC1之间差异的遗传小鼠模型，这两个相关的 对小鼠和小鼠的肿瘤和病毒感染具有强大但独特贡献的亚型 人类。