Development and function of inflammatory innate lymphoid cells

项目总结/摘要 该项目的目标是了解控制效应淋巴细胞稳定性的机制， 可塑性，以及这种调节如何影响人类健康和疾病。最近的研究表明， 淋巴细胞具有相当大的可塑性。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，暴露于Notch信号可以引起先天性 淋巴细胞可塑性和训练成熟的第2组先天淋巴样细胞（ILC 2），以获得共同产生 大量ILC 2和ILC 3特征性细胞因子，从而将天然ILC 2（nILC 2）转化为 可塑性炎性ILC 2（iILC 2）。我们的新数据表明，这种塑料iILC 2相对富集在 严重难治性哮喘患者的气道。在这个项目中，我们将使用过继转移，染色质 免疫沉淀和RNA测序实验，以探索细胞和分子机制， 其中Notch信号通路增强ILC 2的可塑性。我们还将研究人和小鼠iILC 2的能力， 介导气道炎症和高反应性。最后，我们将研究 成人患者中可塑性iILC 2的形成和对严重难治性哮喘的易感性。 总之，这些实验将揭示控制淋巴细胞谱系稳定性的机制， 可塑性，并将告知有针对性的治疗策略，以治疗哮喘和其他自身免疫性疾病患者 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.