Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.
Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 Project, Graduate School of Medical Science, Yonsei University College of Medicine, Seoul, Korea.
J Allergy Clin Immunol. 2021 May;147(5):1764-1777. doi: 10.1016/j.jaci.2020.11.049. Epub 2021 Jan 28.
Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD).
We aimed to investigate the role of NKT cells in AD development, especially in skin.
Global proteomic and transcriptomic analyses were performed by using skin and blood from human healthy-controls and patients with AD. Levels of CXCR4 and CXCL12 expression in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4 NKT cells was further evaluated in models of mice with AD by using CXCR4-conditionally deficient or CXCL12 transgenic mice.
CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4 NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4 and CD69. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the liver, spleen, and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4 NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4 tissue-resident NKT cells/CXCL12 cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD.
CXCR4 tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.
自然杀伤 T（NKT）细胞是一种非常规的 T 细胞，它连接了先天免疫和适应性免疫。NKT 细胞被认为与特应性皮炎（AD）的发展有关。
我们旨在研究 NKT 细胞在 AD 发展中的作用，特别是在皮肤中的作用。
通过对健康对照者和 AD 患者的皮肤和血液进行全局蛋白质组学和转录组学分析。在人类 AD 和小鼠 AD 模型中分析皮肤 NKT 细胞中 CXCR4 和 CXCL12 的表达水平。通过使用并体和活体成像，进一步评估了 AD 模型中皮肤 CXCR4 NKT 细胞在 CXCR4 条件性缺陷或 CXCL12 转基因小鼠中的作用。
通过全局转录组学和蛋白质组学分析，发现 CXCR4 和其配体 CXCL12 在人类 AD 皮肤中显著上调。CXCR4 NKT 细胞在 AD 皮肤中富集，并且在我们的 AD 小鼠模型中其水平持续升高。变应原诱导的 NKT 细胞参与皮肤过敏炎症。与组织驻留记忆 T 细胞相似，主要的皮肤 NKT 细胞是 CXCR4 和 CD69。不同于肝、脾和淋巴结中的 NKT 细胞，皮肤驻留 NKT 细胞独特地表达 CXCR4。皮肤成纤维细胞是 CXCL12 的主要来源。CXCR4 NKT 细胞优先迁移到 CXCL12 丰富的区域，形成一个富含 CXCR4 的组织驻留 NKT 细胞/CXCL12 细胞簇，在我们的 AD 小鼠模型中的急性和慢性过敏炎症中发展。
CXCR4 组织驻留 NKT 细胞可能形成一个有助于 AD 的生态位，其中 CXCL12 高度表达。
