Differential Roles of the mTOR-STAT3 Signaling in Dermal γδ T Cell Effector Function in Skin Inflammation
Differential Roles of the mTOR-STAT3 Signaling in Dermal γδ T Cell Effector Function in Skin Inflammation
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DOI：
10.1016/j.celrep.2019.05.019
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发表时间：
2019-06-04
期刊：
影响因子：
8.8
通讯作者：
Yan, Jun
中科院分区：
文献类型：
--
作者：
Cai, Yihua;Xue, Feng;Yan, Jun
真皮 γ δ T 细胞在皮肤稳态和炎症中发挥着关键作用。然而，这些细胞被激活的潜在分子机制尚未完全了解。在这里，我们证明了 ra-pamycin (mTOR) 和 STAT3 通路的机制或哺乳动物靶点在真皮 γ δ T 细胞中响应白细胞介素 1 β (IL-1 β) 和 IL-23 等先天刺激而被激活。虽然 mTOR 复合物 1 (mTORC1) 和 mTORC2 对于真皮 γ δ T 细胞增殖至关重要，但 mTORC2 缺陷会导致真皮 γ δ T17 细胞减少。线粒体介导的氧化磷酸化似乎在此过程中至关重要。值得注意的是，虽然 STAT3 通路对于真皮 V gamma 4T17 效应器功能至关重要，但它对于 V gamma 6T17 细胞来说不是必需的。转录因子 IRF-4 激活通过连接 IL-1 beta 和 IL-23 信号传导促进真皮 γ δ T 细胞 IL-17 的产生。真皮 γ δ T 细胞中 mTORC2 的缺失（而非 STAT3）可改善皮肤炎症。综上所述，我们的结果表明 mTOR-STAT3 信号传导差异调节皮肤炎症中的真皮 γ δ T 细胞效应器功能。
Dermal gamma delta T cells play critical roles in skin homeostasis and inflammation. However, the underlying molecular mechanisms by which these cells are activated have not been fully understood. Here, we show that the mechanistic or mammalian target of ra-pamycin (mTOR) and STAT3 pathways are activated in dermal gamma delta T cells in response to innate stimuli such as interleukin-1 beta (IL-1 beta) and IL-23. Although both mTOR complex 1 (mTORC1) and mTORC2 are essential for dermal gamma delta T cell proliferation, mTORC2 deficiency leads to decreased dermal gamma delta T17 cells. It appears that mitochondria-mediated oxidative phosphorylation is critical in this process. Notably, although the STAT3 pathway is critical for dermal V gamma 4T17 effector function, it is not required for V gamma 6T17 cells. Transcription factor IRF-4 activation promotes dermal gamma delta T cell IL-17 production by linking IL-1 beta and IL-23 signaling. The absence of mTORC2 in dermal gamma delta T cells, but not STAT3, ameliorates skin inflammation. Taken together, our results demonstrate that the mTOR-STAT3 signaling differentially regulates dermal gamma delta T cell effector function in skin inflammation.