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

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

项目成果

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ANA C ANDERSON其他文献

ANA C ANDERSON的其他文献

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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:
Steroid hormone regulation of immune responses
类固醇激素对免疫反应的调节
  • 批准号:
    10189531
  • 财政年份:
    2018
  • 资助金额:
    $ 51.8万
  • 项目类别:
Steroid hormone regulation of immune responses
类固醇激素对免疫反应的调节
  • 批准号:
    10418699
  • 财政年份:
    2018
  • 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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  • 批准号:
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