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逆转SKI-SMAD4介导的抑制对于T_H17细胞的分化至关重要

Song Zhang^1,2, Motoki Takaku³, Liyun Zou^1,2

¹Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599, USA.

|October 27, 2017

概括

转化生长因子β (TGFβ) 通过逆转SKI-SMAD4抑制RORγt,使T辅助细胞17 (T_H17) 的分化成为可能. 这揭示了控制T_H17细胞的关键机制,并确定了SKI-SMAD4轴作为治疗点.

科学领域:

免疫学
细胞和分子生物学
疾病的分子机制

背景情况:

辅助T细胞17 (T_H17) 对于宿主防御,炎症和自身免疫非常重要.
转化生长因子β (TGFβ) 对于T_H17细胞的分化至关重要,通常与互白素-6结合使用.
TGFβ促进T_H17分化的精确分子机制尚不清楚.

研究的目的:

阐明TGFβ促进T_H17细胞分化的机制.
研究SKI-SMAD4复合体在调节RORγt表达和T_H17分化中的作用.
确定T_H17介导疾病的潜在治疗点.

主要方法:

野生型和SMAD4缺乏T细胞的T细胞分化分析.
在异位SMAD4或SKI表达上研究RORγt表达和T_H17分化.
蛋白质组分析以确定蛋白质相互作用 (SMAD4和SKI).
在Rorc位点评估基因素乙化.

主要成果:

缺乏SMAD4的T细胞分化为T_H17细胞,独立于TGFβ信号传递,依赖于RORγt.
TGFβ可以逆转SKI-SMAD4介导的与视网膜酸受体相关的孤儿受体γt (RORγt) 表达.
在TGFβ刺激时,SMAD4与转录抑制剂SKI相互作用.
SKI通过SMAD4控制Rorc位点和T_H17分化中的素乙化.

结论:

通过破坏SKI-SMAD4复合体,TGFβ可以使T_H17细胞分化,从而逆转RORγt抑制.
SKI-SMAD4轴是RORγt表达和T_H17细胞分化的一个关键调节器.
针对SKI-SMAD4轴为T_H17细胞驱动的自身免疫和炎症性疾病提供了潜在的治疗策略.

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