The canonical Hippo pathway components modulate the differentiation of lamina propria regulatory T cells and T helper 17-like regulatory T cells in mouse colitis.

IF 4.8 4区 医学 Q2 IMMUNOLOGY
Liuqing Ge, Min Xu, Meifang Huang, Shaoping Liu, Zhidai Zhou, Ziqin Xia, Shouquan Dong, Qiu Zhao, Ruiping Zhu, Feng Zhou
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引用次数: 0

Abstract

Regulatory T cells (Tregs) ameliorate inflammatory bowel diseases. However, their plasticity is not completely understood. In this study using a mouse colitis model, Tregs and T helper 17 (Th17)-like Tregs were detected and sorted using flow cytometry, followed by transcriptome sequencing, real-time RT-PCR, and flow cytometry to analyze the mRNA profiles of these cells. Treg plasticity was evaluated by in vitro differentiation assays. The immunosuppressive activities of Tregs and Th17-like Tregs were assessed in an adoptive transfer assay. We found Tregs-derived Th17-like Tregs in inflamed colonic lamina propria (LP). LP Th17-like Tregs expressed higher Th17-related cytokines and lower immunosuppressive cytokines compared with LP Tregs. Notably, Tregs expressed higher Yes-associated protein 1 (YAP1) but lower transcriptional coactivator with PDZ‑binding motif (TAZ) than Th17-like Tregs. Verteporfin-mediated inhibition of YAP1 activity enhanced Th17-like Treg generation, whereas IBS008739-induced TAZ activation did not affect Th17-like Treg generation. Besides, verteporfin enhanced while IBS008739 suppressed the differentiation of Th17-like Tregs into Th17 cells. Furthermore, YAP1 activated STAT5 signaling in Tregs, whereas YAP1 and TAZ activated STAT3 and STAT5 signaling in Th17-like Tregs. Compared with Tregs, Th17-like Tregs were less efficacious in ameliorating colitis. Therefore, YAP1 suppressed Treg differentiation into Th17-like Tregs. Both YAP1 and TAZ inhibited the differentiation of Th17-like Tregs into Th17 cells. Therefore, YAP1 and TAZ probably maintain the immunosuppressive activities of Tregs and Th17-like Tregs in colitis.

在小鼠结肠炎中,典型 Hippo 通路成分可调节固有膜调节性 T 细胞和 T 辅助 17 样调节性 T 细胞的分化。
调节性 T 细胞(Tregs)可改善炎症性肠病。然而,人们对它们的可塑性还不完全了解。本研究使用小鼠结肠炎模型,用流式细胞术检测和分选Tregs和T辅助细胞17(Th17)样Tregs,然后用转录组测序、实时RT-PCR和流式细胞术分析这些细胞的mRNA谱。体外分化试验评估了 Treg 的可塑性。在收养性转移试验中评估了Tregs和Th17样Tregs的免疫抑制活性。我们在发炎的结肠固有膜(LP)中发现了Tregs衍生的Th17样Tregs。与 LP Tregs 相比,LP Th17-like Tregs 表达较高的 Th17 相关细胞因子和较低的免疫抑制细胞因子。值得注意的是,与Th17样Tregs相比,Tregs表达较高的Yes相关蛋白1(YAP1),但表达较低的具有PDZ结合基调的转录辅激活因子(TAZ)。Verteporfin介导的YAP1活性抑制增强了Th17样Treg的生成,而IBS008739诱导的TAZ激活并不影响Th17样Treg的生成。此外,verteporfin 增强了 Th17-like Tregs 向 Th17 细胞的分化,而 IBS008739 则抑制了 Th17-like Tregs 向 Th17 细胞的分化。此外,YAP1能激活Tregs中的STAT5信号,而YAP1和TAZ能激活Th17样Tregs中的STAT3和STAT5信号。与Tregs相比,Th17样Tregs改善结肠炎的效果较差。因此,YAP1抑制了Treg向Th17样Treg的分化。YAP1和TAZ都能抑制Th17样Tregs分化为Th17细胞。因此,YAP1和TAZ可能维持了Tregs和Th17样Tregs在结肠炎中的免疫抑制活性。
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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
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