Ezh2 控制自然杀伤 T 细胞的发育，而这些细胞会导致自发性哮喘样病变。
Ezh2 controls development of natural killer T cells, which cause spontaneous asthma-like pathology.
机构信息
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
出版信息
J Allergy Clin Immunol. 2019 Aug;144(2):549-560.e10. doi: 10.1016/j.jaci.2019.02.024. Epub 2019 Mar 7.
BACKGROUND
Natural killer T (NKT) cells express a T-cell receptor that recognizes endogenous and environmental glycolipid antigens. Several subsets of NKT cells have been identified, including IFN-γ-producing NKT1 cells, IL-4-producing NKT2 cells, and IL-17-producing NKT17 cells. However, little is known about the factors that regulate their differentiation and respective functions within the immune system.
OBJECTIVE
We sought to determine whether the polycomb repressive complex 2 protein enhancer of zeste homolog 2 (Ezh2) restrains pathogenicity of NKT cells in the context of asthma-like lung disease.
METHODS
Numbers of invariant natural killer T (iNKT) 1, iNKT2, and iNKT17 cells and tissue distribution, cytokine production, lymphoid tissue localization, and transcriptional profiles of iNKT cells from wild-type and Ezh2 knockout (KO) iNKT mice were determined. The contribution of NKT cells to development of spontaneous and house dust mite-induced airways pathology, including airways hyperreactivity (AHR) to methacholine, was also assessed in wild-type, Ezh2 KO, and Ezh2 KO mice lacking NKT cells.
RESULTS
Ezh2 restrains development of pathogenic NKT cells, which induce spontaneous asthma-like disease in mice. Deletion of Ezh2 increased production of IL-4 and IL-13 and induced spontaneous AHR, lung inflammation, mucus production, and IgE. Increased IL-4 and IL-13 levels, AHR, lung inflammation, and IgE levels were all dependent on iNKT cells. In house dust mite-exposed animals Ezh2 KO resulted in enhanced AHR that was also dependent on iNKT cells.
CONCLUSION
Ezh2 is a central regulator of iNKT pathogenicity and suppresses the ability of iNKT cells to induce asthma-like pathology.
背景
自然杀伤 T (NKT) 细胞表达一种 T 细胞受体，可识别内源性和环境糖脂抗原。已经鉴定出几种 NKT 细胞亚群，包括产生 IFN-γ 的 NKT1 细胞、产生 IL-4 的 NKT2 细胞和产生 IL-17 的 NKT17 细胞。然而，对于调节其在免疫系统中的分化和各自功能的因素知之甚少。
目的
我们试图确定多梳抑制复合物 2 蛋白增强子的锌指蛋白 2 (Ezh2) 是否在哮喘样肺部疾病的情况下抑制 NKT 细胞的致病性。
方法
测定野生型和 Ezh2 敲除 (KO) iNKT 小鼠中不变自然杀伤 T (iNKT) 1、iNKT2 和 iNKT17 细胞的数量以及组织分布、细胞因子产生、淋巴组织定位和 iNKT 细胞的转录谱。还评估了 NKT 细胞对自发性和屋尘螨诱导的气道病理，包括对乙酰甲胆碱的气道高反应性 (AHR) 的贡献，在野生型、Ezh2 KO 和缺乏 NKT 细胞的 Ezh2 KO 小鼠中进行了评估。
结果
Ezh2 抑制致病性 NKT 细胞的发育，这些细胞在小鼠中诱导自发性哮喘样疾病。Ezh2 的缺失增加了 IL-4 和 IL-13 的产生，并诱导了自发性 AHR、肺炎症、粘液产生和 IgE。增加的 IL-4 和 IL-13 水平、AHR、肺炎症和 IgE 水平均依赖于 iNKT 细胞。在屋尘螨暴露的动物中，Ezh2 KO 导致增强的 AHR，这也依赖于 iNKT 细胞。
结论
Ezh2 是 iNKT 致病性的核心调节剂，可抑制 iNKT 细胞诱导哮喘样病理的能力。
Zotero 插件