Enforced Expression of Gata3 in T Cells and Group 2 Innate Lymphoid Cells Increases Susceptibility to Allergic Airway Inflammation in Mice
Enforced Expression of Gata3 in T Cells and Group 2 Innate Lymphoid Cells Increases Susceptibility to Allergic Airway Inflammation in Mice
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DOI：
10.4049/jimmunol.1301888
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发表时间：
2014-02-15
影响因子：
4.4
通讯作者：
Hendriks, Rudi W.
中科院分区：
文献类型：
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作者：
KleinJan, Alex;Wolterink, Roel G. J. Klein;Hendriks, Rudi W.
过敏性哮喘的呼吸道炎症反应反映了先天免疫系统的阈值反应，包括第2组先天淋巴样细胞(ILC2)，然后是适应性Th2细胞介导的反应。转录因子GATA3对Th2细胞和ILC2的分化都是必不可少的。我们研究了T细胞和ILC2中GATA3表达增强对小鼠过敏性呼吸道炎症(AAI)易感性的影响。我们使用了CD2-GATA3转基因(TG)小鼠，在CD2启动子的驱动下GATA3的表达增强，CD2启动子在T细胞和ILC2发育期间都是活跃的。在没有佐剂的轻度AAI模型中，对CD2-GATA3TG小鼠和野生型(WT)小鼠进行了分析。在WT对照组中，暴露OVA变应原不会引起炎症反应，而CD2-GATA3TG小鼠表现出明显的AAI，并增加了支气管肺泡灌洗液中IL-5和IL-13的水平。同样，在粉尘螨驱动的哮喘中，CD2-GATA3TG小鼠比WT仔鼠更容易受到AAI的影响，因此ILC2和Th2细胞都是支气管肺泡灌洗液和肺组织中IL-5和IL-13的重要细胞来源。与WT小鼠相比，CD2-GATA3TG小鼠ILC2的数量增加，ILC2表达高水平的IL-33R，并对IL-4、IL-5和IL-13的早期产生有显著贡献。CD2-GATA3TG小鼠也有一组独特的IL-33反应性非B/非T淋巴样细胞表达干扰素-γ。因此，强制表达GATA3足以增强Th2和ILC2的活性，并导致在轻度暴露于吸入无害的AGS后增加AAI的易感性，否则会诱导Ag耐受。
Airway inflammation in allergic asthma reflects a threshold response of the innate immune system, including group 2 innate lymphoid cells (ILC2), followed by an adaptive Th2 cell-mediated response. Transcription factor Gata3 is essential for differentiation of both Th2 cells and ILC2. We investigated the effects of enforced Gata3 expression in T cells and ILC2 on the susceptibility of mice to allergic airway inflammation (AAI). We used CD2-Gata3 transgenic (Tg) mice with enforced Gata3 expression driven by the CD2 promoter, which is active both in T cells and during ILC2 development. CD2-Gata3 Tg mice and wild-type (WT) littermates were analyzed in mild models of AAI without adjuvants. Whereas OVA allergen exposure did not induce inflammation in WT controls, CD2-Gata3 Tg mice showed clear AAI and enhanced levels of IL-5 and IL-13 in bronchoalveolar lavage. Likewise, in house dust mite-driven asthma, CD2-Gata3 Tg mice were significantly more susceptible to AAI than WT littermates, whereby both ILC2 and Th2 cells were important cellular sources of IL-5 and IL-13 in bronchoalveolar lavage and lung tissue. Compared with WT littermates, CD2-Gata3 Tg mice contained increased numbers of ILC2, which expressed high levels of IL-33R and contributed significantly to early production of IL-4, IL-5, and IL-13. CD2-Gata3 Tg mice also had a unique population of IL-33-responsive non-B/non-T lymphoid cells expressing IFN-gamma. Enforced Gata3 expression is therefore sufficient to enhance Th2 and ILC2 activity, and leads to increased susceptibility to AAI after mild exposure to inhaled harmless Ags that otherwise induce Ag tolerance.