Molecular regulation of NK cell functional maturation by the transcription factor BACH2

自然杀伤细胞（NK）是一种特殊的免疫细胞类型，形成了对抗癌症和感染的关键第一道防线。NK细胞识别癌细胞和感染的方式与CD8+ T细胞不同。这使得它们作为免疫治疗的替代靶点具有吸引力。迄今为止，临床对NK细胞靶向免疫疗法的反应并不明显，需要更好地了解限制其功能的分子过程。NK细胞存在多种不同的状态，称为功能成熟状态。这对它们控制感染和癌症的能力具有重要意义。我们缺乏对NK细胞功能成熟是如何调节的理解，尽管确定这种机制可能为NK细胞免疫疗法提供新的治疗靶点。在人类中，一种编码转录因子蛋白BACH2的基因的遗传变异与多种自身免疫性和过敏性疾病的易感性有关，当免疫系统经历过度激活时就会引起这种疾病。最近在我们实验室进行的实验表明，BACH2在NK细胞中表达，并负调控其功能成熟，从而影响肿瘤免疫。这项工作的目的是建立BACH2在NK细胞中的功能，测试它是NK细胞功能成熟的关键负调节因子的假设，并测试其对感染和癌症的稳态和免疫反应的影响。我们提出的研究分为三个目标：首先，我们将发现BACH2在正常情况下如何影响NK细胞的行为，以及在感染流感期间，NK细胞可以促进病毒清除和过度炎症。其次，我们将研究BACH2在NK细胞对癌症的反应中的作用，包括在体内存在的NK细胞中，以及在治疗转移到荷瘤宿主时。最后，我们将研究支撑BACH2功能的分子过程，找出BACH2在NK细胞基因组中的结合位置以及它调节的基因。总的来说，这项研究将使人们更好地了解在正常情况下、感染和癌症期间免疫系统的功能是如何被控制的。这可能有助于开发新的疗法，通过抑制或增强炎症、感染和癌症患者的免疫反应来发挥作用。

Natural killer (NK) cells are a specialised immune cell type that form a critical first line of defence against cancer and infection. NK cells recognise cancer cells and infections in a different way to CD8+ T cells. This makes them attractive as alternate targets for immunotherapy. Clinical responses to NK cell-targeted immunotherapies have thus far been modest identifying a need to better understand molecular processes that restrict their function. NK cells exist in a variety of different states, called functional maturation states. These have important implications for their ability to control infections and cancer. We lack an understanding of how NK cell functional maturation is regulated, though identifying such mechanisms may provide new therapeutic targets in NK cell-based immune therapies. In people, genetic variations in a gene that encodes a transcription factor protein called BACH2 are associated with susceptibility to multiple autoimmune and allergic diseases, caused when the immune system undergoes excessive activation. Recent experiments conducted in our laboratories indicate that BACH2 is expressed in NK cells and negatively regulates their functional maturation with consequences for tumour immunity. The purpose of this work is to establish the function of BACH2 in NK cells, testing the hypothesis that it is a critical negative regulator of NK cell functional maturation and testing its consequences for homeostasis and immune responses to infection and cancer. Our proposed study is organised into three aims: Firstly, we will find out how BACH2 affects the behaviour of NK cells under normal conditions, and during infection with influenza, where NK cells can contribute to both viral clearance and excessive inflammation. Secondly, we will examine the effect of BACH2 in NK cell responses against cancer, both in NK cells existing within the body, and upon therapeutic transfer into tumour-bearing hosts. Finally, we will examine the molecular processes that underpin the function of BACH2, finding out where BACH2 binds in NK cell genomes and which genes it regulates. Collectively, this research will enable a better understanding of how the function of the immune system is controlled to under normal conditions and during infections and cancer. This may enable development of new therapies that work by either restraining or enhancing immune responses in individuals with inflammation, infections and cancer.