Transcriptional Regulation of Innate-Like T Cells

先天淋巴细胞包括 ILC 和先天样 NKT/MAIT/gamma-delta T 淋巴细胞 典型地获得 Th1、Th2 或 Th17 样辅助程序以及组织驻留特性 在骨髓或胸腺发育期间。在这方面，他们与他们的 适应性 T 细胞对应物，出生时是幼稚的并再循环，并且仅获得组织驻留 暴露于病原体和细胞因子后的效应特性。我们的研究重点是了解 在非常不同的背景下控制这些群体并行发展的不同机制。 虽然我们之前报道过转录因子 (TF) PLZF 是先天性的常见特征 决定其先天发育命运的谱系，该项目重点关注监管层 在先天和中差异控制辅助谱系特异性 TF Gata-3、T-bet 和 RORgt 的增强子 适应性淋巴细胞，重点是 NK 细胞。我们开发了一种表观遗传学方法来识别 这些增强子和我们生成的增强子报告菌株用于特异性操纵先天性 和适应性人群。这种方法的优点是表观遗传标记出现得更早，并且 比它们调节的 TF 更稳定。它们还提供了更多的复杂性和特异性来剖析 这些发展计划。为了支持这种方法，我们最近确定了一个专用的 ILC2- 特定增强子和生成的缺乏该增强子的小鼠来剖析先天增强子的各自贡献 以及过敏性气道炎症模型中的适应性 2 型反应。在这里，我们将应用这个新的 阐明 NK 细胞与其他 I 类细胞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， 混淆了先前的研究。具体目标将（SA#1）识别 NK 的候选增强子 通过全基因组生物信息搜索的发育途径； (SA#2) 验证这些增强子 通过 CRISPR 删除体内； (SA#3) 生成增强子报告菌株，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异性提供新颖的见解 先天淋巴细胞，并产生新的工具来探讨它们各自在体内平衡和 肿瘤、感染和自身免疫性疾病。 相关性（参见说明）： 我们的研究调查了最近发现的所谓先天淋巴细胞群体。这些细胞发挥作用 在免疫反应的早期，并为维持组织健康和调节做出重大贡献 肿瘤、感染、过敏和自身免疫性疾病的反应。具体来说，我们开发新的 遗传小鼠模型将有助于定义 NK 细胞和 ILC1（两种相关细胞）之间的差异 对小鼠和小鼠的肿瘤和病毒感染发挥有效但独特作用的亚型 人类。

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.