T-bet and STAT6 Coordinately Suppress the Development of IL-9-Mediated Atopic Dermatitis-Like Skin Inflammation in Mice
T-bet and STAT6 Coordinately Suppress the Development of IL-9-Mediated Atopic Dermatitis-Like Skin Inflammation in Mice
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T-bet 和 STAT6 协同抑制小鼠 IL-9 介导的特应性皮炎样皮肤炎症的发展
DOI：
10.1016/j.jid.2020.08.029
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Nakajima H
中科院分区：
文献类型：
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作者：
Makita S;Takatori H;Matsuki A;Kawashima;Iwata A;Tanaka S;Nakagomi D;Oya Y;Matsumura R;Tamachi T;Suto A;Suzuki K;Hirose K;Nakajima H
T-bet和信号转导和转录激活因子（STAT）6是人类和小鼠辅助性T细胞分化的关键因子。此外，TBX 21（T-bet）和STAT 6基因多态性与过敏性疾病的易感性相关。然而，T-bet和STAT 6在变态反应中相互调节的确切机制仍不清楚。为了确定体内的相互调节，我们研究了T-bet/STAT 6双缺陷（T-bet−/− STAT 6 −/−）小鼠的表型。出乎意料的是，T-bet−/− STAT 6 −/−小鼠自发地发生了严重的皮炎，而T-bet−/−小鼠或STAT 6 −/−小鼠则没有。不仅嗜酸性粒细胞和肥大细胞，而且CD 4 +T细胞也浸润到T-bet−/− STAT 6 −/−小鼠的皮肤中。将T-bet−/− STAT 6 −/−小鼠的CD 4 +T细胞连续转移到严重联合免疫缺陷小鼠中，可诱导皮肤中嗜酸性粒细胞和肥大细胞的积聚，而CD 4 +T细胞的耗竭可改善T-bet−/− STAT 6 −/−小鼠的皮炎。全面的转录组分析显示，IL-9的表达在T-bet−/− STAT 6 −/− CD 4 +T细胞中增强。事实上，IL-9中和作用改善了T-bet−/− STAT 6 −/−小鼠的皮炎。T-bet−/− STAT 6 −/− CD 4 +T细胞表达功能性胸腺基质淋巴细胞生成素受体，并在胸腺基质淋巴细胞生成素刺激下产生大量IL-9。这些结果表明，T-bet和STAT 6协同抑制特应性皮炎样皮肤炎症，可能是通过抑制CD 4 +T细胞中胸腺基质淋巴细胞生成素依赖性IL-9的产生。
T-bet and signal transducer and activator of transcription (STAT) 6 are critical factors for helper T-cell differentiation in humans and mice. Additionally, polymorphisms inTBX21(T-bet) andSTAT6are associated with the susceptibility of allergic diseases. However, precise mechanisms of the reciprocal regulation between T-bet and STAT6 in allergy remain unclear. To determine the reciprocal regulation in vivo, we investigated the phenotype of T-bet/STAT6 double-deficient (T-bet−/−STAT6−/−) mice. Unexpectedly, T-bet−/−STAT6−/−mice but not T-bet−/−mice or STAT6−/−mice spontaneously developed severe dermatitis. Not only eosinophils and mast cells but also CD4+T cells infiltrated into the skin of T-bet−/−STAT6−/−mice. Adoptive transfer of CD4+T cells of T-bet−/−STAT6−/−mice into severe combined immunodeficient mice induced the accumulation of eosinophils and mast cells in the skin, whereas depletion of CD4+T cells ameliorated the dermatitis in T-bet−/−STAT6−/−mice. Comprehensive transcriptome analyses revealed that IL-9 expression was enhanced in T-bet−/−STAT6−/−CD4+T cells. Indeed, IL-9 neutralization ameliorated the dermatitis in T-bet−/−STAT6−/−mice. T-bet−/−STAT6−/−CD4+T cells expressed functional thymic stromal lymphopoietin receptors and produced large amounts of IL-9 on thymic stromal lymphopoietin stimulation. These results indicate that T-bet and STAT6 coordinately suppress atopic dermatitis–like skin inflammation, possibly by inhibiting thymic stromal lymphopoietin–dependent IL-9 production in CD4+T cells.