mTORC2 negatively controls the maturation process of medullary thymic epithelial cells by inhibiting the LTβR/RANK-NF-κB axis
mTORC2 negatively controls the maturation process of medullary thymic epithelial cells by inhibiting the LTβR/RANK-NF-κB axis
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mTORC2通过抑制LT beta R/RANK-NF-kappa B轴负向控制胸腺髓质上皮细胞的成熟过程
DOI：
10.1002/jcp.30192
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发表时间：
2020-12-02
影响因子：
5.6
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
--
作者：
Liang, Zhanfeng;Zhang, Qian;Zhao, Yong
成熟胸腺髓质上皮细胞（mTECs）的分化是诱导中枢免疫耐受的关键。尽管已经研究了雷帕霉素复合物1（mTORC 1）的机制靶点在形成mTEC分化中的关键作用，但是对mTORC 2在mTEC的分化和成熟中的调节作用知之甚少。我们在此报道了TEC特异性消融mTOR的雷帕霉素不敏感伴侣（RICTOR），mTORC 2的关键成分，显著降低胸腺大小和重量，TEC的总细胞数，以及mTEC的细胞数，皮质胸腺上皮细胞减少程度较小。有趣的是，RICTOR缺陷显著加速mTEC成熟过程，如RICTOR缺陷小鼠中成熟mTEC（MHCIIhi、CD 80（+）和Aire（+））与未成熟mTEC（MHCIIlo、CD 80（-）和Aire（-））的比率增加所示。RNA测序结果显示，Rictor缺陷型mTECs的核因子-κ B（NF-κ B）信号通路较野生型mTECs明显改变。我们的研究进一步表明，Rictor缺陷型mTECs表现出NF-κ B受体激活剂（RANK）和β-光敏素受体（LT β R）的表达上调，以及经典和非经典NF-κ B信号通路的活性增加（通过ImageStream和Simple Western测定）。最后，我们的研究结果表明，抑制NF-κ B信号通路可以部分逆转Rictor条件性KO小鼠中mTECs的加速成熟。因此，mTORC 2通过抑制LT β R/RANK-NF-κ B信号轴负性控制mTEC成熟过程的动力学。
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 (MHCIIhi, CD80(+), and Aire(+)) to immature mTECs (MHCIIlo, CD80(-), and Aire(-)) in Rictor-deficient mice. The RNA-sequencing assays showed that the upregulated nuclear factor-kappa B (NF-kappa B) signaling pathway in Rictor-deficient mTECs was one of the obviously altered pathways compared with wild-type mTECs. Our studies further showed that Rictor-deficient mTECs exhibited upregulated expression of receptor activator of NF-kappa B (RANK) and lymphotoxin beta receptor (LT beta R), as well as increased activity of canonical and noncanonical NF-kappa B signaling pathways as determined by ImageStream and Simple Western. Finally, our results showed that inhibition of NF-kappa B 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 LT beta R/RANK-NF-kappa B signal axis.