CIS-REGULATORY CIRCUITS FOR ILC FUNCTION AND PLASTICITY

项目总结 必须在先天免疫系统和获得性免疫系统的细胞中实现微妙的调节平衡，以 有效清除病原体，同时将对邻近组织的损害降至最低。监管方面的缺陷 控制细胞或可溶性介质表达的机制可能会干扰病原体的清除或 导致与自身免疫相关的不受控制的炎症反应。最近的研究表明， 先天免疫系统包括功能相当的辅助性T细胞(Th)，它缺乏抗原特异性 受体和反应增强的动力学和活力的危险信号的病原性侮辱。这个 与之对应的被称为先天淋巴样细胞(ILCs)的细胞也与几种 自身免疫性疾病，包括炎症性肠病(IBD)。在发现驱动的侧写研究中 在R21的支持下，联合绩效指标最近定义了Th-ILC对口单位的监管环境 源自发炎的人粘膜，揭示了一系列常规和超级增强剂，可能 控制关键免疫介质的表达。此外，许多在特定ILC或 TH亚群与自身免疫相关疾病SNPs共定位，提示调节元件可能 重要的是控制附近基因的表达水平，这些基因介导了自身免疫发病机制。尽管 这一进展，以及这些潜在的重要调控元件在细胞类型、激动剂和 疾病特异性基因的表达仍未进行测试。当前项目的目标是解决这些问题 悬而未决的问题，重点是对IL22-IL23R-IL1R1-STAT3轴的调节，这对免疫至关重要 ILC3-Th17对应体的功能，其遗传位点富含与自身免疫相关的SNPs。该公司- PIS还将定义和测试ILC3调节组的关键方面，以控制其向ILC1的功能转换，a 过程与IBD的发病机制有关。为了实现这些目标，我们将利用共同绩效指标的互补性 专业知识。科隆纳博士的实验室发现了几个ILC亚群，并有助于我们理解它们 老鼠和人类的生物学。奥尔茨博士的实验室研究驱动淋巴细胞发育的顺式调节电路 和转型。提出了三个具体目标来检验假设：(I)独特的增强剂集合 对体内细胞类型和激动剂特异性表达IL22和IFNG至关重要，(Ii)疾病的一个亚组- 相关SNPs干扰转录因子结合和增强子功能以改变IL23R、STAT3或IL1R 自身免疫发病过程中ILC3Th17细胞的表达和(Iii)ILC3ILc1的转换需要 完全激活ILC1相关的增强子，保持在ILC3中，反之，退役 ILC3特异的增强子，可能会将它们转换为抑制状态。我们的项目将共同确定关键 主导自身免疫相关基因表达模式的ILC-Th调节体的特征 炎症，最终提供了对表达细胞因子的细胞在发病机制中的独立作用的洞察 开辟了新的治疗途径。

PROJECT SUMMARY A delicate regulatory balance must be achieved in cells of the innate and adaptive immune systems to effectively eliminate pathogens, while minimizing damage in neighboring tissues. Defects in regulatory mechanisms that govern expression of cellular or soluble mediators can interfere with pathogen clearance or lead to unchecked inflammatory responses associated with autoimmunity. Recent studies have revealed that the innate immune system includes functional counterparts of T helper (Th) cells, which lack antigen-specific receptors and respond with enhanced kinetics and vigor to danger signals induced by pathogenic insults. The Th counterparts, called innate lymphoid cells (ILCs), have also been implicated in the pathogenesis of several autoimmune diseases, including inflammatory bowel disease (IBD). In discovery-driven profiling studies supported by an R21, the Co-PIs have recently defined the regulatory landscapes of Th-ILC counterparts derived from inflamed human mucosae, revealing collections of conventional- and super-enhancers that may control the expression of key immune mediators. Moreover, many enhancers that were active in specific ILC or Th subsets co-localized with autoimmune-associated disease SNPs, suggesting the regulatory elements may be important for controlling expression levels of nearby genes that mediate autoimmune pathogenesis. Despite this progress, the precise role of these potentially important regulatory elements in cell type-, agonist-, and disease-specific gene expression remains untested. The goal of the current project is to address these outstanding issues, focusing on regulation of the IL22-IL23R-IL1R1-STAT3 axis, which is critical for immune function of ILC3-Th17 counterparts and whose genetic loci are rich in autoimmune-associated SNPs. The Co- PIs will also define and test key aspects of the ILC3 regulome that control their functional conversion to ILC1, a process implicated in IBD pathogenesis. To achieve these goals, we will leverage the Co-PIs' complementary expertise. Dr. Colonna's lab discovered several ILC subsets and contributed to our understanding of their biology in mice and humans. Dr. Oltz's lab studies cis-regulatory circuits that drive lymphocyte development and transformation. Three specific aims are proposed to test the hypotheses that: (i) unique sets of enhancers are critical for cell type- and agonist-specific expression of IL22 and IFNG in vivo, (ii) a subset of disease- associated SNPs disrupts transcription factor binding and enhancer function to alter IL23R, STAT3, or IL1R expression in ILC3 and Th17 cells during autoimmune pathogenesis, and (iii) ILC3ILC1 conversion requires full activation of ILC1-associated enhancers that remain poised in ILC3 and, conversely, a decommissioning of ILC3-specific enhancers, perhaps converting them to a repressed state. Together, our project will identify key features of the ILC-Th regulomes that dominate expression patterns of genes involved in autoimmune inflammation, providing insights into independent roles of cytokine expressing cells in pathogenesis, ultimately opening new therapeutic avenues.