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

项目总结 产生CD4+IL-17的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，但并不是所有的Th17细胞都驱动疾病。事实上，Th17的两个主要亚型 在小鼠和人类中都被描述为：动态平衡或非致病性(NpTh17)，维持 组织中的稳定状态和炎症或致病的Th17(PTh17)，它们驱动破坏性的组织炎症。 重要的是，npTh17是pTh17的前体，而IL-23是npTh17转化的开关因子 到pTh17。然而，IL-23驱动这种转化的机制还不是很清楚。识别 这些机制将为开发治疗多发性硬化症的新的治疗干预措施提供重要的见解。 转录因子Tcf-1的编码基因Tcf7的遗传变异与疾病有关 在全基因组关联研究中，多发性硬化症的易感性，但潜在的机制仍不清楚。 值得注意的是，TCF-1与Th17生物学有关，但由于相互矛盾的数据，其作用尚不清楚 在T细胞发育缺陷或间接研究TCF-1的模型中产生。使用的小鼠 有条件地删除Tcf7只在成熟的T细胞中存在，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信号来获得致病潜能。事实上，我们有 在体内发现TCF-1在npTh17和pTh17中有不同的调节，IL-23关闭TCF-1 表情。我们的初步数据进一步揭示了一个可能的调节回路，它将IL-23、TCF-1和 内源性糖皮质激素(GC)信号传导。我们已经发现npTh17是类固醇合成的。他们可以生产 GCS反过来维持TCF-1的表达，对抗IL23R信号，并抑制Th17的致病作用。在……里面 相比之下，IL-23关闭了npTh17细胞中类固醇的生成。因此，我们假设TCF-1- 糖皮质激素调节电路决定了IL-23在Th17细胞中的致病性。我们已经产生了 几种可用于研究糖皮质激素受体TCF-1作用的新型条件性基因敲除小鼠 (GR)，以及成熟T细胞特有的细胞内源性类固醇激素生成。我们将使用这些工具来机械地 剖析这一新颖的调节电路。我们提出以下目标：1)明确TCF-1在对抗IL-1中的作用。 23-Th17致病；2)决定糖皮质激素信号如何调节TCF-1的表达，IL23R 信号和Th17致病性；以及3)细胞内源性类固醇合成在对抗Th17中的作用 致病性。 考虑到Tcf7基因变异与Tcf7基因变异与 复发缓解型多发性硬化症(RR-MS)患者对多发性硬化症的易感性和使用GC治疗复发的情况。

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).