Dynamic regulation of human immunity by Interferon Regulatory Factor 8 (IRF8)

干扰素调节因子8（IRF8）对人体免疫力的动态调节

• 批准号: MR/W01677X/1
• 负责人: Venetia Bigley
• 金额: $ 273.72万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW01677X%2F1
• 关键词: Dynamic; regulation; human; immunity; Interferon

The immune system is our major defence against bacterial infections, viruses and cancer. It is also responsible for inflammatory diseases and plays a major role in age-related degenerative diseases. The immune system is made of many different cells including granulocytes, monocytes, dendritic cells and lymphocytes. All of these are created in the bone marrow from stem cells through the process of blood formation, known as haematopoiesis. This research project aims to understand how haematopoiesis controls immune responses.Haematopoiesis is a complex process. The production of different cells depends upon specific genes that are turned on and off by proteins that bind to DNA, known as transcription factors. Production is finely tuned to allow the immune system to respond to specific threats, a process known as demand-adaptation. Interferon Regulatory Factor 8 (IRF8) is a key transcription factor in haematopoiesis but how it is regulated and how it controls other genes is not well understood. I have previously found that people with a faulty IRF8 gene are unable to make dendritic cells, and in some cases also monocytes, but have a large excess of neutrophils. The level of imbalance depends upon how much IRF8 activity is present, strongly suggesting that IRF8 is the master control switch. If there are insufficient dendritic cells, then it is not possible to develop immune memory to past viral infections and vaccines. Lack of neutrophils lead to frequent and often fatal bacterial infections, while too many can cause inflammation in the lungs and suppress natural immune responses to cancer. Correctly balanced haematopoiesis is therefore critical to maintaining health and responding effectively to disease.In this project I will study how IRF8 is regulated and how it maintains the balance of haematopoiesis by controlling the activity of other genes. I will use cutting-edge techniques that reveal these processes within single cells. I will also use genetic variation in the IRF8 gene to study how differences between individuals affect immunity.The project has four Aims. In the first Aim, I will use single cell techniques to map the developmental pathways of immune cells, identify regions of DNA important for regulating IRF8 in these pathways, and define the genes that IRF8 controls. In Aim 2, I will extend these techniques to analyse haematopoietic stem cells from patients with sepsis caused by infection, or those with breast cancer, conditions that are both associated with extreme imbalance of immune cells. This will allow me to identify the mechanisms that drive the imbalance and find ways that these could be controlled for medical benefit. In Aim 3, I will gather samples from people with severe mutations in the IRF8 gene in order to understand how different parts of IRF8 are required for it to function correctly. Finally, in Aim 4, I will study natural genetic variation in the region of the IRF8 gene to create a detailed map of how the activity of the IRF8 gene is controlled. It is likely that as a population, we have a wide range of IRF8 responses and that genetic variation gives us diversity as a species in the face of infection and other challenges. Together, this work will define the precise role of IRF8 in human haematopoiesis and how this controls immune cell development. I will discover the factors that control IRF8 and map the network of genes influenced by IRF8 in at each stage of immune cell development. This will identify ways to modify haematopoiesis to achieve better immune responses to infections, vaccines and immune therapy, to suppress harmful immune reactions, and to augment immunity to cancer.

免疫系统是我们针对细菌感染，病毒和癌症的主要防御。它还导致炎症性疾病，并在与年龄相关的退行性疾病中起主要作用。免疫系统由许多不同的细胞制成，包括粒细胞，单核细胞，树突状细胞和淋巴细胞。所有这些都是从干细胞到血液形成过程的骨髓中产生的，称为造血。该研究项目旨在了解造血者如何控制免疫反应。大足气虫是一个复杂的过程。不同细胞的产生取决于与DNA结合的蛋白（称为转录因子）打开和关闭的特定基因。对生产进行了精心调整，以使免疫系统能够应对特定的威胁，这是一种被称为需求适应的过程。干扰素调节因子8（IRF8）是造血的关键转录因子，但是如何调节它以及如何控制其他基因。我以前已经发现，IRF8基因有故障的人无法制作树突状细胞，在某些情况下也无法产生单核细胞，但中性粒细胞过多。不平衡的水平取决于存在多少IRF8活动，强烈表明IRF8是主控制开关。如果树突状细胞不足，则不可能产生免疫记忆来过去的病毒感染和疫苗。缺乏嗜中性粒细胞会导致频繁且经常致命的细菌感染，而太多会导致肺部炎症并抑制对癌症的自然免疫反应。因此，正确平衡的造血对维持健康和有效疾病至关重要。在该项目中，我将研究如何调节IRF8以及如何通过控制其他基因的活性来保持造血的平衡。我将使用在单个单元格中揭示这些过程的尖端技术。我还将使用IRF8基因中的遗传变异来研究个体之间的差异如何影响免疫力。该项目具有四个目标。在第一个目标中，我将使用单细胞技术来绘制免疫细胞的发育途径，确定DNA的DNA区域对于调节这些途径中的IRF8很重要，并定义IRF8控制的基因。在AIM 2中，我将扩展这些技术，以分析由感染或乳腺癌引起的败血症患者或乳腺癌患者的造血干细胞，这些疾病都与免疫细胞的极端失衡有关。这将使我能够确定驱动不平衡的机制，并找到可以控制医疗利益的方法。在AIM 3中，我将收集来自IRF8基因严重突变的人的样本，以了解如何正确运行IRF8的不同部分。最后，在AIM 4中，我将研究IRF8基因区域中的自然遗传变异，以详细介绍如何控制IRF8基因的活性。作为一个人群，我们可能会有广泛的IRF8反应，并且遗传变异使我们成为感染和其他挑战的物种的多样性。这项工作将共同定义IRF8在人造血中的精确作用，以及这如何控制免疫细胞的发育。我将发现在免疫细胞发育的每个阶段，控制IRF8并绘制受IRF8影响的基因网络的因素。这将确定修饰造血的方法，以更好地对感染，疫苗和免疫治疗，抑制有害的免疫反应以及增强对癌症的免疫力的更好的免疫反应。

项目成果

PAMI Syndrome: Two Cases of an Autoinflammatory Disease with an ALPS-Like Phenotype.

• DOI: 10.1007/s10875-022-01265-x
• 发表时间: 2022-07
• 期刊: JOURNAL OF CLINICAL IMMUNOLOGY
• 影响因子: 9.1
• 作者: Cox, Fionnuala;Bigley, Venetia;Irvine, Alan;Leahy, Ronan;Conlon, Niall
• 通讯作者: Conlon, Niall

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia.

• DOI: 10.1182/blood.2021015036
• 发表时间: 2022-10-27
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Tirtakusuma, Ricky;Szoltysek, Katarzyna;Milne, Paul;Grinev, Vasily V.;Ptasinska, Anetta;Chin, Paulynn S.;Meyer, Claus;Nakjang, Sirintra;Hehir-Kwa, Jayne Y.;Williamson, Daniel;Cauchy, Pierre;Keane, Peter;Assi, Salam A.;Ashtiani, Minoo;Kellaway, Sophie G.;Imperato, Maria R.;Vogiatzi, Fotini;Schweighart, Elizabeth K.;Lin, Shan;Wunderlich, Mark;Stutterheim, Janine;Komkov, Alexander;Zerkalenkova, Elena;Evans, Paul;McNeill, Hesta;Elder, Alex;Martinez-Soria, Natalia;Fordham, Sarah E.;Shi, Yuzhe;Russell, Lisa J.;Pal, Deepali;Smith, Alex;Kingsbury, Zoya;Becq, Jennifer;Eckert, Cornelia;Haas, Oskar A.;Carey, Peter;Bailey, Simon;Skinner, Roderick;Miakova, Natalia;Collin, Matthew;Bigley, Venetia;Haniffa, Muzlifah;Marschalek, Rolf;Harrison, Christine J.;Cargo, Catherine A.;Schewe, Denis;Olshanskaya, Yulia;Thirman, Michael J.;Cockerill, Peter N.;Mulloy, James C.;Blair, Helen J.;Vormoor, Josef;Allan, James M.;Bonifer, Constanze;Heidenreich, Olaf;Bomken, Simon
• 通讯作者: Bomken, Simon

Guidelines for mouse and human DC generation.

• DOI: 10.1002/eji.202249816
• 发表时间: 2023-11
• 期刊: European journal of immunology
• 影响因子: 5.4

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.

• DOI: 10.1084/jem.20220275
• 发表时间: 2023-02-06
• 期刊: The Journal of experimental medicine

Lineage switching of the cellular distribution of BRAFV600E in multisystem Langerhans cell histiocytosis.

• DOI: 10.1182/bloodadvances.2021006732
• 发表时间: 2023-05-23
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Milne, Paul;Bomken, Simon;Slater, Olga;Kumar, Ashish;Nelson, Adam;Roy, Somak;Velazquez, Jessica;Mankad, Kshitij;Nicholson, James;Yeomanson, Dan;Grundy, Richard;Kamal, Ahmed;Penn, Anthony;Pears, Jane;Millen, Gerard;Morland, Bruce;Hayden, James;Lam, Jason;Madkhali, Maymoon;MacDonald, Jamie;Singh, Preeti;Pagan, Sarah;Rodriguez-Galindo, Carlos;Minkov, Milen;Donadieu, Jean;Picarsic, Jennifer;Allen, Carl;Bigley, Venetia;Collin, Matthew
• 通讯作者: Collin, Matthew