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.
J Allergy Clin Immunol. 2019 Aug;144(2):549-560.e10. doi: 10.1016/j.jaci.2019.02.024. Epub 2019 Mar 7.
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.
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.
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.
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.
Ezh2 is a central regulator of iNKT pathogenicity and suppresses the ability of iNKT cells to induce asthma-like pathology.
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。
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。
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。
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。
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。
