Interferon regulatory factor 8 activity in human haematopoisis and immunity

免疫系统是我们抵御细菌感染、病毒和癌症的主要防御系统。它也是炎症性疾病的原因，并在与年龄相关的退行性疾病中发挥重要作用。免疫系统由许多不同的细胞组成，包括粒细胞、单核细胞、树突细胞和淋巴细胞。所有这些都是在骨髓中由干细胞通过血液形成过程（称为造血）产生的。造血细胞的输出在健康状态下受到严格的调节，但当免疫系统受到挑战时，造血细胞可以适应需求。造血是一个复杂的过程。不同细胞的产生取决于特定的基因，这些基因由与DNA结合的蛋白质（称为转录因子）打开和关闭。生产被微调，以允许免疫系统对特定的威胁做出反应，这一过程被称为需求适应。干扰素调节因子8（IRF8）是造血中的关键转录因子，但其如何被调节以及如何控制其他基因尚不清楚。IRF8基因有缺陷的人不能制造树突细胞，在某些情况下也不能制造单核细胞，但有大量过量的中性粒细胞。不平衡的程度取决于IRF8活性的多少，这强烈表明IRF8是主控制开关。如果树突状细胞不足，那么就不可能对过去的病毒感染和疫苗产生免疫记忆。缺乏中性粒细胞会导致频繁且往往致命的细菌感染，而过多的中性粒细胞会导致肺部炎症并抑制对癌症的自然免疫反应。因此，正确平衡的造血对于维持健康和有效应对疾病至关重要。在这个项目中，我将研究IRF8是如何调节的，以及它如何通过控制其他基因的活性来维持造血的平衡。我将使用尖端技术来揭示单细胞内的这些过程。我还将使用IRF8基因的遗传变异来研究IRF8活性的缺陷如何影响造血调控机制。

The immune system is our major defense 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. The output of haematopoietic cells is tightly regulated in health, but can be adapted to meet demand when the immune system is challenged.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. 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 deficiencies in IRF8 activity impact the mechanisms regulating haematopoiesis.