Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid
Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid
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DOI：
10.1016/j.jaci.2018.12.1018
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发表时间：
2019-06-01
影响因子：
14.2
通讯作者：
Akdis, Cezmi A.
中科院分区：
文献类型：
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作者：
Morita, Hideaki;Kubo, Terufumi;Akdis, Cezmi A.
背景：第 2 组先天淋巴细胞 (ILC2) 在过敏性气道炎症的诱导和恶化中发挥着关键作用。因此，阐明 ILC2 激活调节机制已受到广泛关注。虽然先天性淋巴细胞分为 3 个主要亚群，反映了辅助效应 T 细胞亚群，但调节性 T 细胞的对应亚群尚未得到很好的表征。 目的：我们试图确定诱导调节性先天淋巴细胞 (ILCregs) 的因素。 方法：通过 RNA 测序和流式细胞术分析使用视黄酸 (RA) 从 ILC2s 诱导的 IL-10(+) ILCregs。在健康受试者和慢性鼻窦炎伴鼻息肉患者的人鼻组织以及房尘螨或盐水处理小鼠的肺组织中评估了 ILCreg。结果：RA 诱导人 ILC2 分泌 IL-10，但不诱导 2 型细胞因子分泌。 IL-10(+) ILCregs是通过RA刺激从ILC2s转化而来，表达调节性T细胞样特征，表达IL-10、细胞毒性T淋巴细胞相关蛋白4和CD25，并下调2型效应器相关标记，例如T(H)2细胞和ST2上的趋化受体同源分子，并抑制CD4(+) T细胞和ILC2s的活化。在健康受试者的鼻组织或经盐水处理的小鼠的肺组织中很少检测到 ILCregs，但在患有鼻息肉的慢性鼻窦炎患者的鼻组织和经房尘螨处理的小鼠的肺组织中，ILCregs 的数量有所增加。在体内 2 型炎症期间以及体外 IL-13 的作用下，气道上皮细胞中的 RA 合成酶上调。结论：我们已经确定了 RA 将 ILC2 转化为 ILCreg 的独特的免疫调节和抗炎途径。气道上皮细胞和 ILC2 之间的相互作用在 ILCreg 的生成中发挥着重要作用。
Background: Group 2 innate lymphoid cells (ILC2s) play critical roles in induction and exacerbation of allergic airway inflammation. Thus clarification of the mechanisms that underlie regulation of ILC2 activation has received significant attention. Although innate lymphoid cells are divided into 3 major subsets that mirror helper effector T-cell subsets, counterpart subsets of regulatory T cells have not been well characterized.Objective: We sought to determine the factors that induce regulatory innate lymphoid cells (ILCregs).Methods: IL-10(+) ILCregs induced from ILC2s by using retinoic acid (RA) were analyzed with RNA-sequencing and flow cytometry. ILCregs were evaluated in human nasal tissue from healthy subjects and patients with chronic rhinosinusitis with nasal polyps and lung tissue from house dust mite- or saline-treated mice.Results: RA induced IL-10 secretion by human ILC2s but not type 2 cytokines. IL-10(+) ILCregs, which were converted from ILC2s by means of RA stimulation, expressed a regulatory T cell-like signature with expression of IL-10, cytotoxic T lymphocyte-associated protein 4, and CD25, with downregulated effector type 2-related markers, such as chemoattractant receptor-homologous molecule on T(H)2 cells and ST2, and suppressed activation of CD4(+) T cells and ILC2s. ILCregs were rarely detected in human nasal tissue from healthy subjects or lung tissue from saline-treated mice, but numbers were increased in nasal tissue from patients with chronic rhinosinusitis with nasal polyps and in lung tissue from house dust mite-treated mice. Enzymes for RA synthesis were upregulated in airway epithelial cells during type 2 inflammation in vivo and by IL-13 in vitro.Conclusion: We have identified a unique immune regulatory and anti-inflammatory pathway by which RA converts ILC2s to ILCregs. Interactions between airway epithelial cells and ILC2s play an important roles in the generation of ILCregs.