Gene circuits programming IL-17 production in innate lymphocytes

描述(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来模拟：第一，负责启动与分化状态相关的基因的转录因子(TF)的快速和瞬时启动；第二，与直接前体状态或交替的细胞命运选择相关的基因的抑制；以及第三，与分化状态相关的基因的长期诱导。与免疫基因组计划(ImmGen)联合产生的成熟先天TCR+胸腺细胞亚群转录本纲要的初稿与该模型相匹配，并预测其他具有共同功能但作用于独特解剖位置的先天淋巴样细胞(ILCs)受具有主题共性的调控网络控制。为了揭示指定关键的先天性免疫功能的基因调控网络，我们建议测试预测的调控模块，这些模块控制T细胞产生先天性IL-17(？17)。IL-17家族细胞因子是炎症反应的中心效应因子，在人类自身免疫紊乱中起重要作用。虽然适应性T细胞产生IL-17的规则已经被广泛研究，但如何调节特殊的ILC亚群产生IL-17尚不清楚。T？？17细胞是细菌感染期间IL-17的主要来源，其产生IL-17的能力是在胸腺中编程的。控制编程的基因调控网络尚不清楚。负责T？？17分化的建筑蓝图一旦被发现，就可以作为理解所有效应器ILC发展的指南。对先天T效应分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：第一，鉴定定义分化的T？？17状态的TF的初始波和其中明显的初始编程的祖细胞；第二，系统地定位靶T？？17基因的Tf调节基因的占位；第三，从基因调控网络的顶端对网络(基因KO小鼠和病原体挑战)进行扰动，然后进行影响分析，以确定网络中基因模块的功能互连。到目前为止，对决定T？？17细胞命运的调控网络中主要基因节点的功能鉴定揭示了五个基本转录因子(TF)：SOX13、SOX4、ROR？T、TCF1和LEF1，其中只有一个是ROR？T。缺乏Sox13或Sox4的小鼠T？？17分化受损。缺乏TCF1的小鼠产生高分泌IL-17的T细胞，而LEF1的表达是双相的，不包括IL-17天生的效应器。因此，这五个因子构成了天然产生IL-17的核心调节因子，它们嵌入到其他ILC效应器程序中，支持共同的基因网络蓝图产生ILC效应器的预测，并了解它们相互关联的功能将是潜在的炎症性疾病靶向免疫治疗的核心。

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.