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和类似于先天的NKT/Mait/Gamma-delta T淋巴细胞 特征是获取Th1-，Th2-或Th17样辅助程序以及居民居民的特性 在骨髓或胸腺发育期间。在这方面，它们与他们的根本差异 自适应T细胞对应物，天真和再循环天生，仅获得组织居民 暴露于病原体和细胞因子后的效应特性。我们的研究重点是理解 在非常不同的情况下控制这些人群并行发展的不同机制。 虽然我们以前报道说转录因子（TF）PLZF是先天的常见签名 该项目指导其先天发育的命运，该项目着重于监管层 具有不同控制辅助谱系特异性TFS GATA-3，T-BET和RORGT的增强剂 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 这些增强剂，我们生成了增强器记者菌株，用于专门操纵先天性 和自适应种群。这种方法的优点是表观遗传标记出现较早，并且 比它们调节的TF更稳定。他们还提供了更复杂和特异性以剖析 这些发展计划。为了支持这种方法，我们最近确定了专门的ILC2- 缺乏这种增强剂的特定增强剂和产生的小鼠可以剖析先天的相对贡献 在过敏性气道注射模型中的自适应2型反应。在这里，我们将应用这个新的 阐明NK细胞与其他组I之间的身份和关系问题的方法 淋巴细胞表达密切相关的特性和一定程度的可塑性 混杂的先前研究。具体目标（SA＃1）确定NK的候选增强子 通过全基因组生物信息学搜索的发展途径； （SA＃2）在 通过CRISPR删除的体内； （SA＃3）生成专门识别和 操纵NK细胞。这些研究将提供有关组1的复杂性和特异性的新见解 先天淋巴细胞，并生成新的工具来探究其在体内平衡和中的贡献 肿瘤，感染和自身免疫性条件。 相关性（请参阅说明）： 我们的研究研究了最近发现的所谓先天淋巴细胞的人群。这些细胞起作用 免疫反应的早期，为维持组织健康和调节提供了重大贡献 肿瘤，感染，过敏和自身免疫性条件的反应。具体来说，我们开发了新的 遗传小鼠模型将有助于定义NK细胞和ILC1之间的差异，两个相关 对小鼠和病毒感染产生潜力但有明显贡献的亚型 人类。