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首页> 外文期刊>Journal of cellular physiology. >mTORC2 negatively controls the maturation process of medullary thymic epithelial cells by inhibiting the LTβR/ RAN K-NF-kappaB axis
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mTORC2 negatively controls the maturation process of medullary thymic epithelial cells by inhibiting the LTβR/ RAN K-NF-kappaB axis

机译：mTORC2消极控制成熟过程髓的胸腺上皮细胞抑制LTβR /跑K-NF-kappaB轴

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The differentiation of mature medullary thymic epithelial cells (mTECs) is critical for the induction of central immune tolerance. Although the critical effect of mechanistic target of rapamycin complex 1 (mTORC1) in shaping mTEC differentiation has been studied, the regulatory role of mTORC2 in the differentiation and maturation of mTECs is poorly understood. We herein reported that TEC-specific ablation of a rapamycin-insensitive companion of mTOR (RICTOR), a key component of mTORC2, significantly decreased the thymus size and weight, the total cell number of TECs, and the cell number of mTECs with a smaller degree of reduced cortical thymic epithelial cells. Interestingly, RICTOR deficiency significantly accelerated the mTEC maturation process, as indicated by the increased ratios of mature mTECs (MHCII~hi, CD80~+, and Aire~+) to immature mTECs (MHCII~lo, CD80~-, and Aire~-) in R/ctor-deficient mice. The RNA-sequencing assays showed that the upregulated nuclear factor-kappaB (NF-kappaB) signaling pathway in R/ctor-deficient mTECs was one of the obviously altered pathways compared with wild-type mTECs. Our studies further showed that R/ctor-deficient mTECs exhibited upregulated expression of receptor activator of NF-kappaB (RANK) and lymphotoxin β receptor (LTβR), as well as increased activity of canonical and noncanonical NF-kappaB signaling pathways as determined by ImageStream and Simple Western. Finally, our results showed that inhibition of NF-kappaB signaling pathways could partially reverse the accelerated maturation of mTECs in Rictor conditional KO mice. Thus, mTORC2 negatively controls the kinetics of the mTEC maturation process by inhibiting the LTbetaR/RANK-NF-kappaB signal axis.
机译：的分化成熟髓胸腺上皮细胞(mTECs)是至关重要的中枢免疫耐受的诱导。机械的关键作用的目标在塑造mTEC雷帕霉素复杂1 (mTORC1)分化研究,监管mTORC2分化和的作用成熟的mTECs了解甚少。在此报道,TEC-specific消融rapamycin-insensitive mTOR的同伴(RICTOR),mTORC2的关键组成部分,明显降低胸腺尺寸和重量,细胞数量的tec, mTECs的细胞数量以一个较小的程度的降低皮质胸腺上皮细胞。缺乏显著加速mTEC成熟的过程,所表示的增加成熟的mTECs比率(MHCII ~你好,CD80 ~ +,和亚耳河~ +)不成熟mTECs (MHCII ~瞧,CD80 ~ -,和亚耳河~ -)R / ctor-deficient老鼠。RNA-sequencing化验表明,调节核factor-kappaB (NF-kappaB)信号通路在R / ctor-deficient mTECs之一显然通路而改变野生型mTECs。R / ctor-deficient mTECs调节展出NF-kappaB表达受体的激活(排名)和淋巴毒素β受体(LTβR)增加活动的规范经典之中NF-kappaB信号通路由ImageStream和简单的西方。最后,我们的结果表明,抑制NF-kappaB信号通路可能部分反向mTECs的加速成熟Rictor条件KO小鼠。消极的控制mTEC的动力学通过抑制成熟过程LTbetaR / RANK-NF-kappaB信号轴。

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