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Mechanisms Controlling Regulatory T cell Effector Function in IBD

Mechanisms Controlling Regulatory T cell Effector Function in IBD
IBD 中调节性 T 细胞效应功能的控制机制
批准号:
10001469
负责人:
ROBIN D HATTON
金额:
$52.95万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-19 至 2022-08-31

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中文摘要
翻译
项目总结 IBD调节性T细胞效应功能的调控机制。炎症性肠病的发病机制 疾病(IBD)的特征是对肠道微生物区系成分的免疫失调。从老鼠身上发现的 IBD的模型和最近的人类遗传学研究强调了免疫调节的关键的、非多余的作用 细胞因子IL-10在维持肠道免疫稳态中的作用我们的实验室表明,Foxp3+调节性T细胞 (Treg)细胞是肠道中IL-10的主要来源。然而,IL-10只会产生 由Treg细胞的一个子集--定义为‘效应器’(E)Treg细胞。在使用IL-10的初步研究中 转基因报告小鼠模型对分离的T细胞转录差异的研究 根据IL-10的表达,我们确定DNA结合因子Gfi1是IL10基因的中心抑制因子 表达于所有亚群的CD4T细胞,包括Treg细胞。GFI1似乎通过相互作用直接作用于两者 通过间接抑制Prdm1(Blimp1)的转录,Prdm1(Blimp1)是 IL 10在Treg细胞中的表达。此外,Gfi1还抑制其他似乎对eTreg功能至关重要的基因, 提示Gfi1可能在调节eTreg细胞分化中起关键作用。最后,我们有 确定了诱导Foxp3+Treg细胞表达IL-10的细胞因子信号。从本质上讲,IL-10 Treg细胞表达缓慢,需要激活细胞因子信号来抑制Gfi1的表达 转录IL10作为eTreg细胞编程的一部分。这可以解释为什么T细胞表达IL-10 主要局限于处于稳态的肠道,在那里对微生物区系的持续反应提供了一种状态 受控的炎症和促进IL-10发展的促炎细胞因子的来源- 表达eTreg细胞。我们假设肠道中的炎症信号超过了Gfi1介导的抑制 ETreg细胞发育和Gfi1表达的调节将影响Treg的保护能力 炎症环境中的细胞-在很大程度上是通过调节IL-10的表达来实现的。此外,我们假设 Gfi1通过抑制IL-10维持CD4T效应细胞的致病表型,从而抑制 GFI1会将致病T细胞转化为产生IL-10的保护性T细胞,从而改善肠道 疾病。在这里,我们将定义Gfi1抑制小鼠和人Treg细胞中IL-10的机制,并 我们将进行原则证明研究,以检验调节失调对IBD发病机制的影响 T细胞表达Gfi1的研究细胞因子对Gfi1-Blimp1调控机制的研究进展 通过T细胞控制IL-10表达的轴将有助于更好地理解 预防IBD,并将为发现内源性IL-2的新治疗方法提供基础。 10可以上调,增强eTreg细胞的分化和功能,治疗IBD。
英文摘要
PROJECT SUMMARY Mechanisms Controlling Regulatory T Cell Effector Function in IBD. The pathogenesis of inflammatory bowel disease (IBD) is characterized by immune dysregulation to components of the enteric microbiota. Findings from mouse models of IBD and recent human genetic studies highlight a critical, non-redundant role for the immunoregulatory cytokine IL-10 in the maintenance of intestinal immune homeostasis. Our lab has shown that Foxp3+ regulatory T (Treg) cells are, overwhelmingly, the major source of IL-10 in the intestines. However, IL-10 is only produced by a subset of Treg cells—defined as ‘effector’ (e)Treg cells. In preliminary studies that used an IL-10 transgenic reporter mouse model to explore differences between transcriptomes of T cells separated on the basis of expression of IL-10, we identified the DNA-binding factor Gfi1 as a central repressor of Il10 gene expression in all subsets of CD4 T cells, including Treg cells. Gfi1 appears to act both directly, via interactions with the Il10 locus, and indirectly, by repressing transcription of Prdm1 (Blimp1), which is a trans-activator of Il10 in Treg cells. Additionally, Gfi1 represses other genes that appear to be central to eTreg function, suggesting that Gfi1 may play a key role in regulating the differentiation of eTreg cells. Finally, we have identified cytokine signals that induce the expression of IL-10 by Foxp3+ Treg cells. In essence, IL-10 expression by Treg cells is Iatent and requires activating cytokine signals that repress Gfi1 to derepress transcription of Il10 as part of eTreg cell programming. This could explain why IL-10 expression by T cells is largely restricted to the intestines at homeostasis, where on-going responses to the microbiota provide a state of controlled inflammation and a source of pro-inflammatory cytokines that promote the development of IL-10– expressing eTreg cells. We hypothesize that inflammatory signals in the gut override Gfi1-mediated repression of eTreg cell development and that modulation of Gfi1 expression will impact the protective capabilities of Treg cells in an inflammatory environment—in large part through modulation of IL-10 expression. Further, we posit that Gfi1 maintains a pathogenic phenotype in CD4 T effector cells by repressing IL-10, such that inhibition of Gfi1 will convert pathogenic T cells to IL-10–producing protective T cells, thereby ameliorating intestinal disease. Herein, we will define mechanisms by which Gfi1 represses IL-10 in murine and human Treg cells and we will perform proof-of-principle studies to examine the impact on IBD pathogenesis of dysregulated expression of Gfi1 by T cells. The delineation of mechanisms by which cytokines modulate the Gfi1–Blimp1 axis to control IL-10 expression by T cells will lead to a better understanding of homeostatic networks that prevent IBD, and will provide a basis for discovery of novel therapeutic approaches by which endogenous IL- 10 can be up-regulated, and the differentiation and function of eTreg cells enhanced, to treat IBD.
期刊论文(1)
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DOI: 10.15252/embj.2021109803
发表时间: 2023-04-17
期刊: The EMBO journal
影响因子: --
作者: []
通讯作者:
Mechanisms Controlling the Development and Function of Intestinal Effector Treg cells
Gene Regulatory Networks Controlling Effector and Regulatory T Cell Balance in IBD
Effector cell gene regulation by Egr factors
Effector cell gene regulation by Egr factors
国内基金
海外基金
Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
  • 批准号:
    2022J011295
  • 项目类别:
    省市级项目
  • 资助金额:
    10.0万元
  • 批准年份:
    2022
  • 负责人:
    王亚伟
  • 依托单位:
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究