Orchestration of PI3K-dependent transcriptional programmes by the transcription factor BACH2

转录因子 BACH2 协调 PI3K 依赖性转录程序

• 批准号: BB/N007794/1
• 负责人: Rahul Roychoudhuri
• 金额: $ 62.12万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN007794%2F1
• 关键词: Orchestration; PI3K; dependent; transcriptional; programmes

CD8+ T cells powerfully coordinate immune responses against intracellular infections and cancer. During immune responses, CD8+ T cells proliferate and differentiate into effector cells that promote elimination of target cells. Effector cells are short-lived and this enables restoration of normal immune function upon resolution of infection. However, a fraction of cells escape this fate and persist to form long-lived memory cells. Memory cells provide a durable self-renewing source of target-specific cells and can persist for decades following infection to generate more efficient secondary responses upon reinfection. CD8+ T cells also become terminally differentiated or exhausted in response to chronic infections and cancer and this impairs their function. Our previous work has identified a key molecular pathway, termed the phosphoinositide 3-kinase (PI3K) pathway, that powerfully regulates CD8+ T cell differentiation. Activation of the PI3K pathway drives widespread changes in gene expression to promote effector differentiation and prevent the formation of memory cells. Mechanisms by which the PI3K pathway causes changes in gene expression are not fully understood. In this study, we will investigate how the PI3K pathway controls the function of a class of proteins called transcription factors (TFs). TFs bind to regulatory regions within DNA and modulate gene expression to control cellular differentiation. We have recently found that the PI3K pathway controls the function of a transcription factor, BACH2, through a process called phosphorylation. We will investigate this new molecular axis, determining how the PI3K pathway regulates the function of BACH2 to control CD8+ T cell responses. Our experimental approach is divided into three components: 1) We will determine the function of BACH2 in regulating CD8+ T cell responses to infection. To do this, we will use a mouse model in which BACH2 is specifically deleted in CD8+ T cells and study immune responses following infection with experimental pathogens. 2) We will determine how the PI3K pathway controls the function of BACH2 to regulate immune responses to infection using a new mouse model in which BACH2 cannot be phosphorylated. We will also determine how BACH2 phosphorylation regulates BACH2 function at a molecular level. 3) We will test the contribution of BACH2 to PI3K-mediated transcriptional programmes in CD8+ T cells. To achieve this, we will utilise mouse genetics to specifically manipulate the PI3K pathway, and regulated transcription factors in CD8+ T cells, measuring consequences of these experimental manipulations on global gene expression and corresponding this data with analyses of transcription factor binding throughout the genome. This work will extend our understanding of how the PI3K pathway exerts such pervasive control over CD8+ T cell differentiation and provide insights into how external cues control gene expression to shape the outcome of immune responses. This will provide targets for development of new vaccine approaches and immune-based therapies for chronic infections and cancer.

CD 8 + T细胞能够有效协调免疫反应，对抗细胞内感染和癌症。在免疫应答期间，CD 8 + T细胞增殖并分化成促进靶细胞消除的效应细胞。效应细胞是短命的，这使得在感染消退后能够恢复正常的免疫功能。然而，一小部分细胞逃脱了这种命运，并坚持形成长寿的记忆细胞。记忆细胞提供了一个持久的自我更新的目标特异性细胞的来源，并可以持续几十年后感染，以产生更有效的二次反应后再感染。CD 8 + T细胞也会在慢性感染和癌症中发生终末分化或衰竭，这会损害它们的功能。 我们以前的工作已经确定了一个关键的分子途径，称为磷脂酰肌醇3-激酶（PI 3 K）途径，有力地调节CD 8 + T细胞分化。PI 3 K通路的激活驱动基因表达的广泛变化，以促进效应分化并防止记忆细胞的形成。PI 3 K通路引起基因表达变化的机制尚未完全了解。在这项研究中，我们将研究PI 3 K通路如何控制一类称为转录因子（TF）的蛋白质的功能。TF结合到DNA内的调节区域并调节基因表达以控制细胞分化。我们最近发现PI 3 K通路通过一个称为磷酸化的过程控制转录因子BACH 2的功能。我们将研究这个新的分子轴，确定PI 3 K通路如何调节BACH 2的功能，以控制CD 8 + T细胞反应。我们的实验方法分为三个部分：1）我们将确定BACH 2在调节CD 8 + T细胞对感染的应答中的功能。为此，我们将使用一种小鼠模型，其中BACH 2在CD 8 + T细胞中特异性缺失，并研究实验病原体感染后的免疫反应。 2)我们将确定PI 3 K通路如何控制BACH 2的功能，以调节感染的免疫反应，使用一种新的小鼠模型，其中BACH 2不能磷酸化。我们还将确定BACH 2磷酸化如何在分子水平上调节BACH 2功能。 3)我们将测试BACH 2对CD 8 + T细胞中PI 3 K介导的转录程序的贡献。为了实现这一目标，我们将利用小鼠遗传学来特异性地操纵PI 3 K通路，并调节CD 8 + T细胞中的转录因子，测量这些实验操作对全局基因表达的影响，并将这些数据与整个基因组中转录因子结合的分析相对应。 这项工作将扩展我们对PI 3 K通路如何对CD 8 + T细胞分化施加如此普遍的控制的理解，并提供对外部线索如何控制基因表达以塑造免疫应答结果的见解。这将为慢性感染和癌症的新疫苗方法和免疫疗法的开发提供目标。

项目成果

BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.

• DOI: 10.1038/ni.3753
• 发表时间: 2017-07
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Afzali B;Grönholm J;Vandrovcova J;O'Brien C;Sun HW;Vanderleyden I;Davis FP;Khoder A;Zhang Y;Hegazy AN;Villarino AV;Palmer IW;Kaufman J;Watts NR;Kazemian M;Kamenyeva O;Keith J;Sayed A;Kasperaviciute D;Mueller M;Hughes JD;Fuss IJ;Sadiyah MF;Montgomery-Recht K;McElwee J;Restifo NP;Strober W;Linterman MA;Wingfield PT;Uhlig HH;Roychoudhuri R;Aitman TJ;Kelleher P;Lenardo MJ;O'Shea JJ;Cooper N;Laurence ADJ
• 通讯作者: Laurence ADJ

Lineage relationship of CD8(+) T cell subsets is revealed by progressive changes in the epigenetic landscape.

CD8（+）T细胞亚群的谱系关系通过表观遗传景观的进行性变化揭示。

• DOI: 10.1038/cmi.2015.32
• 发表时间: 2016-07
• 期刊: Cellular & molecular immunology
• 影响因子: 24.1
• 作者: Crompton JG;Narayanan M;Cuddapah S;Roychoudhuri R;Ji Y;Yang W;Patel SJ;Sukumar M;Palmer DC;Peng W;Wang E;Marincola FM;Klebanoff CA;Zhao K;Tsang JS;Gattinoni L;Restifo NP
• 通讯作者: Restifo NP

Ionic immune suppression within the tumour microenvironment limits T cell effector function.

• DOI: 10.1038/nature19364
• 发表时间: 2016-09-22
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Eil, Robert;Vodnala, Suman K.;Clever, David;Klebanoff, Christopher A.;Sukumar, Madhusudhanan;Pan, Jenny H.;Palmer, Douglas C.;Gros, Alena;Yamamoto, Tori N.;Patel, Shashank J.;Guittard, Geoffrey C.;Yu, Zhiya;Carbonaro, Valentina;Okkenhaug, Klaus;Schrump, David S.;Linehan, W. Marston;Roychoudhuri, Rahul;Restifo, Nicholas P.
• 通讯作者: Restifo, Nicholas P.