Gene circuits programming IL-17 production in innate lymphocytes

基因电路编程先天淋巴细胞中 IL-17 的产生

基本信息

批准号：
8506613
负责人：
Joonsoo Kang
金额：
$ 39.07万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506613
关键词：
Adult Antigen Receptors Applications Grants Architecture Autoimmune Diseases Autoimmunity Bacterial Infections Biological Assay Boxing CD4 Positive T Lymphocytes Cell Differentiation process Cell Lineage Cell Maintenance Cell physiology Cells ChIP-seq Chromatin Chromosome Mapping Complement Development Disease Effector Cell Equilibrium Escherichia coli Family Gene Expression Profile Gene Expression Regulation Generations Genes Genetic Transcription Genome Gut associated lymphoid tissue Hematopoietic Homeostasis Human Immune Immune response Immunity Immunotherapy Inflammatory Inflammatory Response Interleukin-1 Interleukin-17 Interleukin-6 Intestines Klebsiella pneumonia bacterium Knock-out Listeria monocytogenes Location Lung Lymphocyte Lymphoid Lymphoid Cell Maps Mediating Modeling Molecular Mus Mycobacterium tuberculosis Neutrophilia Pattern Process Production Proteins Pulmonary Fibrosis Receptor Signaling Regulation Regulator Genes Reporter Signal Transduction Skin Source Specific qualifier value System T cell differentiation T-Cell Development T-Lymphocyte T-Lymphocyte Subsets Testing Thymus Gland Tissues Transforming Growth Factor beta Variant WNT Signaling Pathway cytokine gene induction genome-wide human disease innate immune function interleukin-22 interleukin-23 member morphogens mucosal site novel pathogen progenitor programs public health relevance receptor stem cell differentiation thymocyte transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Gene transcription dynamics associated with cell lineage differentiation can be modeled on three sequential processes: First, a rapid and transient onset of activities of transcription factors (TFs) responsible for turning on genes associated with differentiated states; second, suppression of genes associated with the immediate precursor state or alternate cell fate choice; and third, long lasting induction of gene associated with differentiated states. The first draft of a compendium of transcriptomes of maturing innate ?¿TCR+ thymocyte subsets produced in conjunction with the Immunological Genome Project (ImmGen) matches the model and predicts that other innate lymphoid cells (ILCs) with shared function, but acting at unique anatomical locations, are controlled by regulatory networks with thematic commonality. To uncover the gene regulatory networks that specify critical innate immune function we propose to test the predicted regulatory modules controlling innate IL-17 production from ?¿ T cells (?¿17). IL-17 family of cytokines has emerged as the central effectors of inflammatory responses contributing to autoimmune disorders in humans. While the rules for IL- 17 production by adaptive T cells are extensively studied how IL-17 production from specialized ILC subsets is regulated is unknown. T?¿17 cells are the primary source of IL-17 during bacterial infection and its capacity for IL-17 production is programmed in the thymus. The gene regulatory network controlling the programming was unknown. The architectural blueprint responsible for T?¿17 differentiation, once discovered, can be used as a guide to understand all effector ILC development. A comprehensive understanding of innate T effector lineage differentiation can be accomplished by three interconnected approaches: First, identification of the initial wave of TFs that define differentiated T?¿17 state and the progenitors in which the initial programming is evident; second, a systematic mapping of TF regulator occupancy of target T?¿17 genes; and third, perturbation of the network (gene KO mice and pathogen challenge) from the apex of the gene regulatory network followed by impact analyses to determine functional interconnectivity of gene modules within the network. Functional characterization of the primary gene nodes in the regulatory network specifying T?¿17 cell fate has so far revealed five essential transcription factors (TFs): SOX13, SOX4, ROR?t, TCF1 and LEF1, of which only one, ROR?t, was previously identified. Mice deficient in Sox13 or Sox4 have impaired T?¿17 differentiation. Mice lacking TCF1 generate T cells with hyper-production of IL-17 while LEF1 expression is biphasic, excluded from IL-17 innate effectors. The five TFs therefore constitute the core regulators of innate IL-17 production and they are embedded in other ILC effector programs, supporting the prediction that a common gene network blueprint generates ILC effectors and understanding their interconnected function will be central to potential targeted immunotherapies of inflammatory disorders.

描述（由申请人提供）：与细胞谱系分化相关的基因转录动力学可以根据三个连续过程进行建模：首先，负责开启与分化状态相关的基因的转录因子（TF）活性的快速且短暂的启动；与直接前体状态或替代细胞命运选择相关的基因的抑制；第三，与分化状态相关的基因的长期诱导。与免疫基因组计划 (ImmGen) 联合产生的 TCR+ 胸腺细胞亚群与模型相匹配，并预测具有共享功能但作用于独特解剖位置的其他先天淋巴细胞 (ILC) 受到具有主题共性的调控网络的控制。指定关键先天免疫功能的基因调控网络，我们建议测试控制先天 IL-17 产生的预测调控模块？ T 细胞 (?17) 细胞因子家族已成为人类自身免疫性疾病炎症反应的核心效应器，而适应性 T 细胞产生 IL-17 的规则主要是研究如何产生 IL-17。专门的 ILC 子集是否受到调节尚不清楚。 17 细胞是细菌感染期间 IL-17 的主要来源，其产生 IL-17 的能力在胸腺中进行编程。控制编程的基因调控网络尚不清楚。 17 分化一经发现，可用作了解所有效应子 ILC 发育的指南对先天 T 效应子谱系分化的全面了解可以通过三种相互关联的方法来完成：首先，识别定义分化 T？ ¿ 17 状态和祖细胞，其中初始编程是明显的；第二，目标 T 的 TF 调节器占用的系统映射； 17 个基因；第三，从基因调控网络的顶端扰动网络（基因 KO 小鼠和病原体攻击），然后进行影响分析，以确定网络中主要基因节点的功能互连性。监管网络指定 T?¿迄今为止，Sox17 细胞命运已经揭示了五种必需的转录因子（TF）：SOX13、SOX4、ROR?t、TCF1 和 LEF1，其中仅一种 ROR?t 先前被鉴定为缺乏 Sox13 或 Sox4 的小鼠具有受损的 T?17 细胞命运。 ¿ 17 缺乏 TCF1 的小鼠产生大量产生 IL-17 的 T 细胞，而 LEF1 表达是双相的，被排除在 IL-17 先天效应子之外，因此这五个 TF 构成先天 IL-17 产生的核心调节因子，并且它们嵌入在 IL-17 中。其他 ILC 效应器程序，支持共同基因网络蓝图生成 ILC 效应器的预测，并了解它们相互关联的功能，这对于炎症性疾病的潜在靶向免疫疗法至关重要。