Mysm1 is a decision checkpoint regulator of Group2 innate lymphoid cell biology

尽管疫苗接种策略的成功应用和卫生标准的提高在过去一百年里大大减少了传染病，但包括哮喘、哮喘恶化在内的慢性病正在迅速增加。第二组先天淋巴样细胞(ILC2s)是新近发现的先天淋巴样细胞，是获得性免疫系统中辅助性T细胞(Th2)的先天对应细胞。重要的是，ILC2与生俱来就致力于2型免疫：ILC2是快速而强大的参与者，能够在短时间内分泌大量标志性细胞因子。因此，ILC2不仅能够放大早期免疫反应，还能引导早期免疫反应，从而协调先天免疫和获得性免疫。重要的是，ILC2活性可以通过支持针对蠕虫感染的防御机制而有益于宿主，但也能够触发免疫病理学，如呼吸道炎症。然而，这种免疫病理的潜在调节机制仍然知之甚少。为了能够对抗解除调节的2型免疫，需要对ILC2生物学有更好的了解，以确定临床感兴趣的新靶点。MYB-like、SWIRM和MPN结构域(Mysm1)是一种具有脱泛素酶活性的DNA结合蛋白。有趣的是，Mysm1的活性与几个对ILC2的发育和功能至关重要的转录决定因素有关。因此，我们的目标是破译Mysm1对ILC2发育的调节作用，并研究Mysm1对ILC2外围抑制的重要性。我们将使用转基因小鼠模型、多色表型、新的成像技术以及2型免疫反应的体外和体内模型来推动这一项目。这里介绍的项目将为ILC2生物学的调控过程提供关键和基本的见解。此外，ILC2生物学的新分子靶点将被揭示，这将对开发对抗解除调节的2型免疫反应的治疗策略感兴趣。

Whereas successfully applied vaccination strategies and improved hygiene standards have led to a significant reduction of infectious diseases within the last hundred years, chronic diseases including asthma, asthma exacerbations but also allergies are rapidly increasing. Group 2 innate lymphoid cells (ILC2s) are a recently identified member of innate lymphoid cells and represent the innate counterpart of T helper 2 cells (Th2) of the adaptive immune system. Importantly, ILC2s are innately committed to type 2 immunity: ILC2s are fast and strong actors and able to secrete large amounts of signature cytokines within a short time period. Thereby ILC2s are able to amplify but also direct early immune responses and thereby orchestrate innate but also adaptive immunity. Importantly, ILC2 activity can be beneficial for the host by supporting defence mechanisms against helminth infections but are as well able to trigger immunopathology such as respiratory inflammation. However, the underlying regulatory mechanisms of this immunopathology are still poorly understood. To be able to counter deregulated type 2 immunity, a better understanding of ILC2 biology is needed to identify novel targets of clinical interest. Myb-like, SWIRM, and MPN domains (Mysm1) is a DNA binding protein with deubiquitinase activity. Interestingly, Mysm1 activity has been linked to several transcriptional determinants important for ILC2 development and function. We therefore aim to decipher the regulatory role of Mysm1 for ILC2 development as well as to investigate the importance of Mysm1 for ILC2 restrain in the periphery. We will use transgenic mouse models, multicolour phenotyping, novel imaging techniques and ex vivo and in vivo models of type 2 immune responses to propel this project forward. The here presented project will provide critical and fundamental insights in regulatory processes of ILC2 biology. Moreover, novel molecular targets of ILC2 biology will be revealed which will be of interest for the development of therapeutic strategies to counter deregulated Type 2 immune responses.