Redistribution of Gata3 by T-bet: a novel mechanism underlying T-cell lineage balance

T-bet 重新分配 Gata3：T 细胞谱系平衡的新机制

• 批准号: BB/L009277/1
• 负责人: Richard Jenner
• 金额: $ 49.49万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL009277%2F1
• 关键词: Redistribution; Gata3; bet; novel; mechanism

Our immune system functions to protect us from infection and keep commensal microorganisms that live on and within our bodies in check. There are a number of components of the immune system. CD4 T cells secrete signals that help other cells control microorganism numbers. CD4 T cells are normally resting but when the cell detects a foreign object, it changes into one of a number of different types of effector cell, each of which activates a different component of the immune response. The type of effector cell it becomes depends on the type of foreign object detected and allows the immune response to tailor itself to different threats. It is also important that the appropriate balance between these different effector types is maintained because excessive activation can lead to allergies (excessive responses to harmless substances) or autoimmune diseases (responses against the body).The changes a T cell undergoes when it detects a foreign object are controlled by transcription factors, proteins which bind to specific sites on DNA and turn on and off near-by genes. Development of different effector cell types is directed by different transcription factors. The research field did believe that only one type of factor was turned on at any time, giving the cell clear directions on what cell type to become. But more recently, a number of research groups have shown that T cells can contain more than one type of factor, potentially pulling the cell in two different directions at once or allowing the cell to switch between effector types. The interplay between the two factors when both are present, for example whether one is dominant over the other or whether the cell adopts characteristics driven by both factors, is unclear but is important to understand how T cells tailor the immune response and how the balance between different effector types is maintained. We have found that when two important T cell transcription factors are present in the same cell, one acts dominantly over the other, blocking its ability to control genes. This suggests that a cell can hedge its bets over the cell type it is to become, following the instructions of the dominant factor but maintaining the potential to switch to the other factor. We will identify the mechanism through which one factor acts dominantly over the other and determine its importance for the control of gene activity, development of the appropriate immune response and for a healthy balance between different T cell effector types. This will open new avenues for research that will lead to the ability to block unwanted cellular activities and eventually allow one cell type to be turned into another for regenerative medicine or therapies to boost immunity or target cancers.

我们的免疫系统的功能是保护我们免受感染，并控制生活在我们体内的微生物。免疫系统有许多组成部分。CD4 T细胞分泌信号，帮助其他细胞控制微生物数量。CD4 T细胞通常处于静息状态，但当细胞检测到异物时，它会变成多种不同类型的效应细胞之一，每种效应细胞都会激活免疫反应的不同成分。它成为的效应细胞的类型取决于检测到的异物的类型，并允许免疫反应针对不同的威胁进行调整。同样重要的是，在这些不同的效应器类型之间保持适当的平衡，因为过度激活可能导致过敏（对无害物质的过度反应）或自身免疫性疾病（对身体的反应）。T细胞在检测到异物时所经历的变化是由转录因子控制的，转录因子是与DNA上的特定位点结合并打开和关闭附近基因的蛋白质。不同效应细胞类型的发育由不同的转录因子指导。研究领域确实认为，在任何时候只有一种类型的因子被打开，给细胞明确的方向，使细胞成为什么类型的细胞。但最近，一些研究小组已经表明，T细胞可以包含多种类型的因子，可能会同时将细胞拉向两个不同的方向，或者允许细胞在效应器类型之间切换。当两种因素都存在时，这两种因素之间的相互作用，例如一种因素是否占主导地位，或者细胞是否采用由两种因素驱动的特征，尚不清楚，但对于理解T细胞如何定制免疫应答以及如何维持不同效应物类型之间的平衡很重要。我们已经发现，当两个重要的T细胞转录因子存在于同一个细胞中时，其中一个对另一个起主导作用，从而阻止其控制基因的能力。这表明细胞可以在它将要成为的细胞类型上进行对冲，遵循主导因素的指示，但保持切换到另一个因素的潜力。我们将确定一种因素对另一种因素起主导作用的机制，并确定其对控制基因活性、发展适当的免疫反应以及不同T细胞效应子类型之间的健康平衡的重要性。这将为研究开辟新的途径，从而能够阻止不必要的细胞活动，并最终使一种细胞类型转化为另一种细胞类型，用于再生医学或疗法，以增强免疫力或靶向癌症。

项目成果

T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex.

T-bet通过介体和超伸长络合物激活Th1基因。

• DOI: 10.1016/j.celrep.2016.05.054
• 发表时间: 2016-06-21
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Hertweck A;Evans CM;Eskandarpour M;Lau JC;Oleinika K;Jackson I;Kelly A;Ambrose J;Adamson P;Cousins DJ;Lavender P;Calder VL;Lord GM;Jenner RG
• 通讯作者: Jenner RG

The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes.

• DOI: 10.1093/nar/gkac258
• 发表时间: 2022-05-06
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Hertweck, Arnulf;Vila de Mucha, Maria;Barber, Paul R.;Dagil, Robert;Porter, Hayley;Ramos, Andres;Lord, Graham M.;Jenner, Richard G.
• 通讯作者: Jenner, Richard G.

The Study of Protein-DNA Interactions in CD4+ T-Cells Using ChIPmentation.

使用 ChIPmentation 研究 CD4 T 细胞中的蛋白质-DNA 相互作用。

• DOI: 10.1007/978-1-0716-1311-5_17
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Hertweck A

T-bet fate mapping identifies a novel ILC1-ILC2 subset in vivo

• DOI: 10.1101/2020.08.21.261073
• 发表时间: 2020-08
• 期刊: bioRxiv
• 作者: Jan-Hendrik Schroeder;N. Garrido-Mesa;T. Zabinski;A. Gallagher;L. Campbell;L. Roberts;É. Stolarczyk;G. Beattie;J. Lo;A. Iseppon;C. M. Heliodoro;R. Reis;RG Jenner;P. Lavender;J. Howard;R. Grencis;H. Helmby;J. Neves;G. Lord

Role and species-specific expression of colon T cell homing receptor GPR15 in colitis.

• DOI: 10.1038/ni.3079
• 发表时间: 2015-02
• 期刊: Nature immunology
• 影响因子: 30.5