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).

项目概要 CD4+ IL-17 产生 T 辅助细胞 (Th17) 是中枢神经系统 (CNS) 自身免疫的已知驱动因素 多发性硬化症 (MS) 中的炎症，但并非所有 Th17 细胞都会导致疾病。事实上，两种主要的 Th17 亚型 已在小鼠和人类中得到描述：稳态或非致病性 (npTh17) 组织和炎症或致病性 Th17 (pTh17) 的稳态，驱动破坏性组织炎症。 重要的是，npTh17 是 pTh17 的前体，并且已知 IL-23 是 npTh17 转化的开关因子 至 pTh17。然而，IL-23 驱动这种转化的机制尚不清楚。识别 这些机制将为开发多发性硬化症的新型治疗干预措施提供重要的见解。 TCF7（编码转录因子 TCF-1 的基因）的遗传变异与疾病相关 全基因组关联研究中发现了 MS 的易感性，但其潜在机制仍不清楚。 值得注意的是，TCF-1 与 Th17 生物学有关，但由于数据相互矛盾，其作用仍不清楚 在 T 细胞发育缺陷或间接研究 TCF-1 的模型中生成。使用鼠标 仅在成熟T细胞中有条件地删除Tcf7，从而具有正常的T细胞发育，我们发现 TCF-1 缺陷的 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 在体内 npTh17 和 pTh17 中受到差异调节，并且 IL-23 关闭 TCF-1 表达。我们的初步数据进一步揭示了连接 IL-23、TCF-1 和 内源性糖皮质激素 (GC) 信号传导。我们发现 npTh17 具有类固醇生成作用。他们可以生产 GC 反过来又维持 TCF-1 表达、对抗 IL23R 信号传导并抑制 Th17 致病性。在 相反，IL-23 会关闭 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 Th17 细胞中 IL-23 驱动的致病性。我们已经生成了 几种新型条件敲除小鼠，我们可以用它们来研究糖皮质激素受体 TCF-1 的作用 (GR)，以及细胞内在类固醇生成，特别是在成熟 T 细胞中。我们将使用这些工具来机械地 剖析这个新颖的调节电路。我们提出以下目标： 1) 明确 TCF-1 在对抗 IL-1 中的作用 23驱动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) 确定细胞内在类固醇生成在对抗 Th17 中的作用 致病性。 鉴于 TCF7 的遗传变异与 对 MS 的易感性以及使用 GC 治疗复发缓解型 MS (RR-MS) 患者的复发。