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

Mysm1 是 Group2 先天淋巴细胞生物学的决策检查点调节因子

• 批准号: 428195095
• 负责人: Dr. Claudia Dürr
• 金额: --
• 依托单位: Institut für Mikrobiologie und Infektionsimmunologie (CBF)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428195095?language=en
• 关键词: Mysm1; decision; checkpoint; regulator; Group2

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.

尽管成功应用的疫苗接种策略和改善的卫生标准在过去一百年内导致传染病的显著减少，但包括哮喘、哮喘急性发作以及过敏在内的慢性疾病正在迅速增加。第2组先天性淋巴样细胞（ILC2）是最近鉴定的先天性淋巴样细胞的成员，并且代表适应性免疫系统的T辅助2细胞（Th2）的先天对应物。重要的是，ILC2天生致力于2型免疫：ILC2是快速和强大的演员，能够在短时间内分泌大量的标志性细胞因子。因此，ILC2能够扩增但也指导早期免疫应答，从而协调先天性免疫和适应性免疫。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对宿主有益，但也能够触发免疫病理学，如呼吸道炎症。然而，这种免疫病理学的潜在调控机制仍然知之甚少。为了能够对抗失调的2型免疫，需要更好地理解ILC2生物学，以确定临床感兴趣的新靶点。Myb样、SWE3和MPN结构域（Mysm1）是具有去泛素化酶活性的DNA结合蛋白。有趣的是，Mysm1活性与ILC2发育和功能的几个重要转录决定因子有关。因此，我们的目标是破译的调控作用Mysm1 ILC2的发展，以及调查的重要性Mysm1 ILC2抑制在周边。我们将使用转基因小鼠模型，多色表型，新的成像技术和2型免疫反应的离体和体内模型，以推动该项目向前发展。这里介绍的项目将提供关键和基本的见解ILC2生物学的调控过程。此外，ILC2生物学的新分子靶点将被揭示，这将对开发对抗失调的2型免疫应答的治疗策略感兴趣。