A TCF1:Glucocorticoid regulatory circuit controls IL-23-driven Th17 pathogenicity

TCF1：糖皮质激素调节电路控制 IL-23 驱动的 Th17 致病性

• 批准号: 10635984
• 负责人: ANA C ANDERSON
• 金额: $ 51.8万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635984
• 关键词: Anabolism; Automobile Driving; Biology; Bypass; CNS autoimmunity; Cells; Central Nervous System; Central Nervous System Diseases; Data; Defect; Development; Disease; Disease susceptibility; Enzymes; Epigenetic Process; Gene Deletion; Genes; Genetic Transcription; Genetic Variation; Glucocorticoid Receptor; Glucocorticoids; Granulocyte-Macrophage Colony-Stimulating Factor; Helper-Inducer T-Lymphocyte; Homeostasis; Human; IL17 gene; Impairment; Inflammation; Inflammatory; Investigation; Knockout Mice; Knowledge; Link; Mature T-Lymphocyte; Mediating; Mediator; Modeling; Multiple Sclerosis; Mus; Pathogenicity; Patients; Predisposition; Prevalence; Regulation; Relapsing-Remitting Multiple Sclerosis; Role; Signal Transduction; Steroid biosynthesis; T-Cell Development; T-Lymphocyte; TCF Transcription Factor; Testing; Thymocyte Selection; Tissues; autoimmune inflammation; beta catenin; clinically relevant; conditional knockout; epigenome; genetic variant; genome wide association study; in vivo; insight; interleukin-23; novel; novel therapeutic intervention; programs; restraint; tool; transcriptome

PROJECT SUMMARY CD4+ IL-17-producing T helper cells (Th17) are known drivers of central nervous system (CNS) autoimmune inflammation in multiple sclerosis (MS), yet not all Th17 cells drive disease. Indeed, two major Th17 subtypes have been described in both mice and humans: homeostatic or non-pathogenic (npTh17) that maintain the steady state in tissue and inflammatory or pathogenic Th17 (pTh17) that drive destructive tissue inflammation. Importantly, npTh17 are precursors of pTh17 and IL-23 is known to be the switch factor for conversion of npTh17 to pTh17. However, the mechanisms by which IL-23 drives this conversion are not well understood. Identifying these mechanisms will provide critical insight for the development of novel therapeutic interventions for MS. Genetic variants in TCF7, the gene encoding the transcription factor TCF-1, have been associated with disease susceptibility in MS in genome-wide association studies, but the underlying mechanisms remain unknown. Notably, TCF-1 has been implicated in Th17 biology, but its role remains unclear due to conflicting data generated in models that have either defective T cell development or that study TCF-1 indirectly. Using mice that conditionally delete Tcf7 only in mature T cells, and thus have normal T cell development, we have found that TCF-1-deficient Th17 cells may not require IL-23R signaling for acquiring pathogenic potential. Indeed, we have found that TCF-1 is differentially regulated in npTh17 and pTh17 in vivo and that IL-23 shuts down TCF-1 expression. Our preliminary data further uncover a putative regulatory circuit that links IL-23, TCF-1, and endogenous glucocorticoid (GC) signaling. We have found that npTh17 are steroidogenic. They can produce GCs, which in turn, sustain TCF-1 expression, oppose IL23R signaling, and restrain Th17 pathogenicity. In contrast, IL-23 shuts down steroidogenesis in npTh17 cells. Accordingly, we hypothesize that a TCF-1- glucocorticoid regulatory circuit determines IL-23-driven pathogenicity in Th17 cells. We have generated several novel conditional knock-out mice with which we can study the role of TCF-1, the glucocorticoid receptor (GR), and cell-intrinsic steroidogenesis specifically in mature T cells. We will use these tools to mechanistically dissect this novel regulatory circuit. We propose the following aims: 1) Define the role of TCF-1 in opposing IL- 23-driven Th17 pathogenicity; 2) Determine how glucocorticoid signaling regulates TCF-1 expression, IL23R signaling, and Th17 pathogenicity; and 3) Determine the role of cell-intrinsic steroidogenesis in opposing Th17 pathogenicity. Our proposed investigation is highly clinically relevant given the association of genetic variants of TCF7 with susceptibility to MS and the use of GCs to treat relapses in patients with relapsing-remitting MS (RR-MS).

项目摘要 CD4+ IL-17产生的T辅助细胞（TH17）是中枢神经系统（CNS）自身免疫的驱动因素 多发性硬化症（MS）的炎症，但并非所有Th17细胞都驱动疾病。确实，两个主要TH17子类型 在小鼠和人类中都描述了：稳态或非致病性（NPTH17） 组织和炎症或致病性TH17（PTH17）中的稳态，这些（PTH17）驱动破坏性组织炎症。 重要的是，NPTH17是PTH17的前体，已知IL-23是NPTH17转化的开关因子 到PTH17。但是，IL-23驱动这种转换的机制尚不清楚。识别 这些机制将为MS开发新的治疗干预措施提供关键的见解。 TCF7（编码转录因子TCF-1的基因）中的遗传变异与疾病有关 全基因组关联研究中MS的敏感性，但潜在的机制仍然未知。 值得注意的是，TCF-1与TH17生物学有关，但由于数据相互矛盾，其作用尚不清楚 在具有缺陷的T细胞发育或间接研究TCF-1的模型中产生。使用鼠标 有条件地仅在成熟的T细胞中删除TCF7，因此具有正常的T细胞发育，我们发现 TCF-1缺陷型TH17细胞可能不需要IL-23R信号传导来获得致病潜力。确实，我们有 发现TCF-1在NPTH17和PTH17中受到差异调节，并且IL-23关闭了TCF-1 表达。我们的初步数据进一步揭示了将IL-23，TCF-1和 内源性糖皮质激素（GC）信号传导。我们发现NPTH17是类固醇生成的。他们可以生产 GCS反过来维持TCF-1表达，反对IL23R信号传导并限制TH17致病性。在 对比，IL-23关闭了NPTH17细胞中的类固醇生成。因此，我们假设TCF-1-- 糖皮质激素调节回路决定了TH17细胞中IL-23驱动的致病性。我们已经生成了 几只新型的条件敲除小鼠，我们可以研究TCF-1的作用，糖皮质激素受体 （GR）和细胞内固醇生成，专门在成熟的T细胞中。我们将使用这些工具机械 解剖这种新颖的调节回路。我们提出以下目的：1）定义TCF-1在相对IL-中的作用 23驱动的Th17致病性； 2）确定糖皮质激素信号如何调节TCF-1表达，IL23R 信号传导和Th17致病性； 3）确定细胞内固醇生成在相对Th17中的作用 致病性。 鉴于TCF7的遗传变异与 对MS的敏感性和使用GC来治疗复发的MS（RR-MS）患者的复发。