Development and function of inflammatory innate lymphoid cells

项目摘要/摘要 这个项目的目标是了解控制效应器淋巴细胞稳定性和 可塑性，以及这一规定如何影响人类健康和疾病。最近的研究表明，先天的 淋巴细胞具有很强的可塑性。潜在的机制，以及对健康和 疾病，仍然未知。我们的初步数据表明，暴露在Notch信号中可以引发先天的 淋巴细胞可塑性和培养成熟的第2组先天淋巴样细胞(ILC2)以获得联合生产的能力 大量的ILC2和ILC3特征的细胞因子，从而将天然的ILC2(NILC2)转化为 塑性炎性ILC2(IILC2)。我们的新数据表明，这种塑料iILC2在 严重难治性哮喘患者的呼吸道。在这个项目中，我们将使用采用转移，染色质 免疫沉淀和RNA测序实验，以探讨其细胞和分子机制 哪个Notch信号引起ILC2可塑性。我们还将研究人类和小鼠iILC2的能力 调节呼吸道炎症和高反应性。最后，我们将调查两者之间的关联 塑料iILC2的发展和成人患者对严重难治性哮喘的易感性。 总之，这些实验将阐明控制淋巴细胞谱系稳定性和 可塑性，并将为治疗哮喘和其他自身免疫患者的靶向治疗策略提供信息 和炎症性疾病。

Project Summary/Abstract The goal of this project is to understand the mechanisms that control effector lymphocyte stability and plasticity, and how this regulation influences human health and disease. Recent studies indicate that innate lymphocytes possess substantial plasticity. The underlying mechanisms, and the implications for health and disease, remain unknown. Our preliminary data indicate that exposure to Notch signaling can elicit innate lymphocyte plasticity and train mature group-2 innate lymphoid cells (ILC2) to acquire the ability to co-produce large amounts of both ILC2- and ILC3- characteristic cytokines, thus converting natural ILC2 (nILC2) into plastic inflammatory ILC2 (iILC2). Our new data suggest that such plastic iILC2 are relatively enriched in the airway of patients with severe refractory asthma. In this project, we will use adoptive transfer, chromatin immunoprecipitation, and RNA sequencing experiments to explore the cellular and molecular mechanisms by which Notch signaling elicits ILC2 plasticity. We will also examine the capability of human and mouse iILC2 to mediate airway inflammation and hyperresponsiveness. Finally, we will investigate the association between the development of plastic iILC2 and the susceptibility to severe refractory asthma in human adult patients. Together, these experiments will shed light on the mechanisms that govern lymphocyte lineage stability and plasticity, and will inform strategies of targeted therapy to treat patients with asthma and other auto-immune and inflammatory disorders.