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
基本信息
- 批准号:10635984
- 负责人:
- 金额:$ 51.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AnabolismAutomobile DrivingBiologyBypassCNS autoimmunityCellsCentral Nervous SystemCentral Nervous System DiseasesDataDefectDevelopmentDiseaseDisease susceptibilityEnzymesEpigenetic ProcessGene DeletionGenesGenetic TranscriptionGenetic VariationGlucocorticoid ReceptorGlucocorticoidsGranulocyte-Macrophage Colony-Stimulating FactorHelper-Inducer T-LymphocyteHomeostasisHumanIL17 geneImpairmentInflammationInflammatoryInvestigationKnockout MiceKnowledgeLinkMature T-LymphocyteMediatingMediatorModelingMultiple SclerosisMusPathogenicityPatientsPredispositionPrevalenceRegulationRelapsing-Remitting Multiple SclerosisRoleSignal TransductionSteroid biosynthesisT-Cell DevelopmentT-LymphocyteTCF Transcription FactorTestingThymocyte SelectionTissuesautoimmune inflammationbeta cateninclinically relevantconditional knockoutepigenomegenetic variantgenome wide association studyin vivoinsightinterleukin-23novelnovel therapeutic interventionprogramsrestrainttooltranscriptome
项目摘要
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。
项目成果
期刊论文数量(0)
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{{ truncateString('ANA C ANDERSON', 18)}}的其他基金
Role of metabolic crosstalk in determining immunity during tumor progression
代谢串扰在肿瘤进展过程中决定免疫的作用
- 批准号:
10718070 - 财政年份:2023
- 资助金额:
$ 51.8万 - 项目类别:
Role of Tim-3 in determining T cell immunity
Tim-3 在决定 T 细胞免疫中的作用
- 批准号:
9024492 - 财政年份:2015
- 资助金额:
$ 51.8万 - 项目类别:
Regulation of stem-like CD8+ T cells and their role in immunotherapy
干细胞样 CD8 T 细胞的调节及其在免疫治疗中的作用
- 批准号:
10400137 - 财政年份:2015
- 资助金额:
$ 51.8万 - 项目类别:
Role of Tim-3 in determining T cell immunity
Tim-3 在决定 T 细胞免疫中的作用
- 批准号:
9210064 - 财政年份:2015
- 资助金额:
$ 51.8万 - 项目类别:
Regulation of stem-like CD8+ T cells and their role in immunotherapy
干细胞样 CD8 T 细胞的调节及其在免疫治疗中的作用
- 批准号:
10211084 - 财政年份:2015
- 资助金额:
$ 51.8万 - 项目类别:
Regulation of stem-like CD8+ T cells and their role in immunotherapy
干细胞样 CD8 T 细胞的调节及其在免疫治疗中的作用
- 批准号:
10622463 - 财政年份:2015
- 资助金额:
$ 51.8万 - 项目类别:
Genetic Elements that Influence Susceptibility to CNS Autoimmunity
影响中枢神经系统自身免疫易感性的遗传因素
- 批准号:
7371005 - 财政年份:2006
- 资助金额:
$ 51.8万 - 项目类别:
Genetic Elements that Influence Susceptibility to CNS Autoimmunity
影响中枢神经系统自身免疫易感性的遗传因素
- 批准号:
7176038 - 财政年份:2006
- 资助金额:
$ 51.8万 - 项目类别:
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