T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production
T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production
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DOI：
10.1016/j.jaci.2016.08.022
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发表时间：
2017-04-01
影响因子：
14.2
通讯作者：
Nakajima, Hiroshi
中科院分区：
文献类型：
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作者：
Matsuki, Ayako;Takatori, Hiroaki;Nakajima, Hiroshi
背景资料：先天性淋巴样细胞（ILC）是在细胞因子和/或alarmin刺激时产生大量细胞因子的免疫细胞的新兴亚群。T-bet在ILC 3s和1型ILCs的发生发展中起关键作用，但T-bet在肺2型固有淋巴样细胞（ILC 2s）中的作用尚不清楚。目的：探讨T-bet在ILC 2介导的气道炎症中的作用。通过使用T-bet缺陷（T-bet（-/-））小鼠来检查T-bet在由IL-33施用诱导的肺ILC 2的发展和气道炎症中的作用。结果：T-bet在肺ILC 2s（定义为表达ST 2或CD 25的Thy1.2（+）Lin（-）细胞）中表达，IFN-γ可增强其表达。尽管T-bet（-/-）小鼠在稳态条件下肺ILC 2的形成是正常的，但IL-33诱导的肺ILC 2蓄积和嗜酸性气道炎症在T-bet（-/-）小鼠中加重。即使在RAG 2（-/-）背景下，由于T-bet的缺乏而加剧的ILC 2和嗜酸性气道炎症的积累也是明显的，这表明在非T/非B群体中表达的T-bet参与抑制IL-33诱导的嗜酸性气道炎症。转录组分析显示，与野生型小鼠相比，T-bet（-/-）小鼠中IL-33刺激的肺ILC中的IL-9表达上调。重要的是，IL-9的中和作用显著减弱了IL-33诱导的肺ILC 2s的积累和T-bet（-/-）小鼠中的嗜酸性粒细胞炎症。结论：T-bet抑制肺ILC 2s产生IL-9，从而抑制IL-33诱导的嗜酸性粒细胞气道炎症。
Background: Innate lymphoid cells (ILCs) are emerging subsets of immune cells that produce large amounts of cytokines upon cytokine and/or alarmin stimulation. Recent studies have shown that T-bet plays pivotal roles in the development of ILC3s and type 1 ILCs; however, the roles of T-bet in lung type 2 innate lymphoid cells (ILC2s) remain unknown.Objective: We sought to determine the role of T-bet in ILC2-mediated airway inflammation.Methods: The expression of T-bet in lung ILCs (defined as Thy1.2(+) Lin(-) cells) was examined. The roles of T-bet in the development of lung ILC2s and airway inflammation induced by IL-33 administration were examined by using T-bet-deficient (T-bet(-/-)) mice. Gene expression profiles of T-bet(-/-) lung ILCs were analyzed by RNA sequencing.Results: T-bet was expressed in lung ILC2s (defined as Thy1.2(+) Lin(-) cells expressing ST2 or CD25) and IFN-gamma enhanced its expression. Although the development of lung ILC2s at steady-state conditions was normal in T-bet(-/-) mice, IL-33-induced accumulation of lung ILC2s and eosinophilic airway inflammation were exacerbated in T-bet(-/-) mice. The exacerbated accumulation of ILC2s and eosinophilic airway inflammation by the absence of T-bet were evident even in a RAG2(-/-) background, suggesting that T-bet expressed in non-T/non-B population is involved in the suppression of IL-33-induced eosinophilic airway inflammation. Transcriptome analysis revealed that IL-9 expression in IL-33-stimulated lung ILCs was upregulated in T-bet(-/-) mice compared with that in wild-type mice. Importantly, neutralization of IL-9 markedly attenuated IL-33-induced accumulation of lung ILC2s and eosinophilic inflammation in T-bet(-/-) mice.Conclusions: T-bet suppresses IL-9 production from lung ILC2s and thereby inhibits IL-33-induced eosinophilic airway inflammation.