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（由适用提供）：与细胞谱系分化相关的基因转录动力学可以在三个顺序过程上进行建模：首先，转录因子活性（TFS）的快速和短暂发作负责打开与分化状态相关的基因；其次，抑制与直接前体状态或替代细胞命运选择相关的基因；第三，与分化状态相关的基因的持久诱导。与免疫基因组项目（IMMGEN）结合产生的先天γδTCR+胸腺集的转录组纲要的初稿，与模型和预测其他先天淋巴样细胞（ILC）相匹配，即共享功能与共享功能，但在独特的解剖学位置中，由唯一的解剖位置进行了控制，由监管性网络控制。为了发现指定关键先天免疫功能的基因调节网络，我们建议测试控制来自γδT细胞的先天IL-17产生的预测调节模块（Tγδ17）。 IL-17细胞因子家族已成为炎症反应的核心作用，导致人类自身免疫性疾病。虽然自适应T细胞生产IL-17的规则被广泛研究了如何调节专业ILC子集的IL-17产生的IL-17产生规则尚不清楚。 Tγδ17细胞是细菌感染过程中IL-17的主要来源，其IL-17产生的能力在胸腺中编程。控制编程的基因调节网络尚不清楚。一旦发现，负责Tγδ17分化的架构蓝图可以用作了解所有效应的ILC发展的指南。可以通过三种相互联系的方法来完成对先天T效应谱系分化的全面理解：首先，鉴定定义分化的Tγδ17状态的TF的初始浪潮和初始编程为证据的祖细胞；其次，靶标Tγδ17基因的TF调节剂的系统映射；第三，网络的扰动（基因KO小鼠和病原体挑战）来自基因调节网络的顶点，然后进行了影响分析，以确定网络中基因模块的功能互连性。到目前为止，指定Tγδ17细胞命运的调节网络中原始基因节点的功能表征揭示了五个基本转录因子（TFS）：SOX13，SOX4，RORγT，TCF1和LEF1，先前仅鉴定出其中一个RORγT。缺乏TCF1的小鼠会产生具有IL-17过度生产的T细胞，而LEF1表达是双相，不包括IL-17先天作用。因此，这五个TF构成了先天IL-17生产的核心调节剂，并且它们嵌入了其他ILC效应程序中，支持这样的预测，即通用基因网络蓝图会产生ILC效应，并且了解其相互联系的功能对于炎症疾病的潜在靶向免疫疗法至关重要。