Transcriptional Regulation of Innate-Like T Cells

先天淋巴细胞包括ILC和先天样NKT/MAIT/γ-δ T淋巴细胞， 特征性地获得Th1、Th2或Th17样辅助程序以及组织驻留特性 在骨髓或胸腺发育过程中。在这方面，他们从根本上不同于他们的 适应性T细胞对应物，它们出生时是幼稚的和再循环的，并且仅获得组织驻留， 暴露于病原体和细胞因子后的效应子特性。我们的研究重点是了解 不同的机制控制着这些人口在非常不同的背景下的平行发展。 虽然我们以前报道过转录因子（TF）PLZF是先天性免疫缺陷的常见标志， 血统，指导他们的先天发展的命运，这个项目的重点是管理层 增强子，其差异控制先天和先天免疫中的辅助谱系特异性TF加塔-3、T-bet和RORgt， 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， 这些增强子和我们产生的增强子报告菌株， 适应人群。这种方法的优点是表观遗传标记出现得更早， 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门的ILC2- 特异性增强子和产生的小鼠缺乏这种增强子，以剖析各自的贡献，先天 和适应性2型反应。在这里，我们将应用这个新的 一种阐明NK细胞与其他I组细胞之间的身份和关系的方法 淋巴细胞，表达密切相关的特性和一定程度的可塑性， 混淆了之前的研究。具体目标将（SA#1）鉴定NK细胞的候选增强子， 通过全基因组生物信息学搜索的发育途径;（SA#2）验证这些增强子在 （SA#3）产生增强子-报告子菌株，其特异性地鉴定并 操纵NK细胞。这些研究将为第1组的复杂性和特异性提供新的见解 先天性淋巴细胞，并产生新的工具，以探测各自的贡献，在稳态和 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的群体。这些细胞 在免疫应答的早期，并在维持组织健康和调节 在肿瘤、感染、过敏和自身免疫性疾病中的反应。具体来说，我们开发新的 遗传小鼠模型，这将有助于确定NK细胞和ILC1之间的差异，两个相关的 在小鼠中对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.