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

• 批准号: 9194376
• 负责人: Joonsoo Kang
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 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/9194376
• 关键词: APEX1 gene; Adult; Anatomy; Antigen Receptors; Applications Grants; Architecture; Autoimmune Diseases; Autoimmunity; Bacterial Infections; Biological Assay; 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 Regulation; Generations; Genes; Genetic Transcription; Genome; Gut associated lymphoid tissue; Hematopoietic; Homeostasis; Human; Immune response; Immunity; Immunologics; Immunotherapy; Impairment; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-17; Interleukin-6; Intestines; Klebsiella pneumonia bacterium; Knock-out; Knockout Mice; Listeria monocytogenes; Location; Lung; Lymphocyte; Lymphoid; Lymphoid Cell; Maps; Mediating; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Neutrophilia; Pathogenicity; Pattern; Process; Production; Proteins; Pulmonary Fibrosis; Receptor Signaling; Regulator Genes; Reporter; SOX13 gene; SOX4 gene; Signal Transduction; Skin; Source; Specific qualifier value; Stem cells; 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; immunoregulation; 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; transcriptome; tumor; whole genome; γδ T cells

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 γδTCR+ 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 γδT cells (Tγδ17). 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. Tγδ17 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 Tγδ17 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 Tγδ17 state and the progenitors in which the initial programming is evident; second, a systematic mapping of TF regulator occupancy of target Tγδ17 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 Tγδ17 cell fate has so far revealed five essential transcription factors (TFs): SOX13, SOX4, RORγt, TCF1 and LEF1, of which only one, RORγt, was previously identified. Mice deficient in Sox13 or Sox4 have impaired Tγδ17 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；成熟先天γδTCR+胸腺细胞亚群转录组纲要的初稿。与免疫基因组计划 (ImmGen) 联合制作的模型与模型相匹配，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，以揭示基因调控网络。为了明确关键的先天免疫功能，我们建议测试控制 γδT 细胞（Tγδ17 细胞因子家族）产生先天 IL-17 的预测调节模块。虽然对适应性 T 细胞产生 IL-17 的规则进行了研究，但 Tγδ17 细胞是细菌过程中 IL-17 的主要来源，但其调节机制尚不清楚。感染及其产生 IL-17 的能力是在胸腺中进行编程的。负责 Tγδ17 分化的基因调控网络一旦被发现，就可以作为理解所有这些的指南。对先天 T 效应子谱系分化的全面理解可以通过三种相互关联的方法来实现：首先，识别定义分化 Tγδ17 状态的 TF 的初始波以及其中初始编程明显的祖细胞；绘制目标 Tγδ17 基因的 TF 调节器占据情况；第三，从基因调节网络的顶点扰动网络（基因 KO 小鼠和病原体攻击），然后进行影响分析以确定网络内基因模块的功能互连性迄今已揭示了决定 Tγδ17 细胞命运的调控网络中主要基因节点的 5 种重要转录因子 (TF)：SOX13、SOX4、RORγt、TCF1 和 LEF1，其中只有一种。先前发现，缺乏 Sox13 或 Sox4 的小鼠会损害 Tγδ17 的分化，而缺乏 TCF1 的小鼠会产生过多的 T 细胞。 IL-17 而 LEF1 表达是双相的，因此被排除在 IL-17 先天效应子之外，因此这五个 TF 构成了先天性 IL-17 产生的核心调节因子，并且它们嵌入到其他 ILC 效应子程序中，支持了共同基因网络蓝图的预测。产生ILC效应子并了解它们相互关联的功能对于炎症性疾病的潜在靶向免疫疗法至关重要。