Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4+CD25+Foxp3+, regulatory T-cell development in mice
Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4+CD25+Foxp3+, regulatory T-cell development in mice
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DOI：
10.1096/fj.13-235408
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发表时间：
2013-10-01
期刊：
影响因子：
4.8
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
--
作者：
Chen, Hui;Zhang, Lianjun;Zhao, Yong
胸腺来源的CD 4（+）CD 25（+）Foxp 3（+）天然调节性T（nT（reg））细胞对于维持外周免疫耐受是必不可少的。驱动未成熟胸腺祖细胞分化为CD 4（+）CD 25（+）Foxp 3（+）nT（reg）细胞的信号通路需要阐明。TSC 1/2复合物是哺乳动物雷帕霉素靶蛋白（mTOR）的关键负调节因子，在胸腺CD 4（+）CD 25（+）Foxp 3（+）nT（reg）细胞发育中的确切作用仍然难以捉摸。在本研究中，我们发现在T细胞特异性TSC 1敲除（TSC 1 KO）小鼠中，胸腺CD 4（+）CD 25（+）Foxp 3（+）nT（reg）细胞的百分比和细胞数量显著增加。然而，TSC 1 KO胸腺中的CD 4（+）CD 25（+）Foxp 3（-）nT（reg）前体水平与野生型小鼠中的水平无法区分。TSC 1 KO CD 4（+）CD 25（+）Foxp 3（+）nT（reg）细胞显示正常细胞死亡，但以STAT 5依赖性方式增强对IL-2的增殖反应。雷帕霉素（Rapa）治疗未能挽救，而是增加了TSC 1 KO和RictorKO小鼠中CD 4（+）CD 25（+）Foxp 3（+）nT（reg）细胞的频率。胸腺CD 4（+）CD 25（+）Foxp 3（+）nT（reg）细胞的百分比和细胞数量在T细胞特异性RictorKO小鼠中显著增加，但在PtenKO小鼠中没有增加。总的来说，我们的研究表明，TSC 1通过Rapa抗性和mTORC 2依赖性信号传导途径在调节胸腺CD 4（+）CD 25（+）Foxp 3（+）nT（reg）-细胞发育中起重要作用。张洪，肖，Y.，Shao，L.，Li，H.，Yin，H.，王，R.，Liu，G.，Corley，D.，杨志，Zhao，Y. TSC 1/2信号复合物的破坏揭示了控制小鼠胸腺CD 4（+）CD 25（+）Foxp 3（+）调节性T细胞发育的检查点。
Thymic-derived CD4(+)CD25(+)Foxp3(+) natural regulatory T (nT(reg)) cells are essential for the maintenance of peripheral immune tolerance. Signaling pathways that drive immature thymic progenitors to differentiate into CD4(+)CD25(+)Foxp3(+) nT(reg) cells need to be elucidated. The precise role of the TSC1/2 complex, a critical negative regulator of mammalian target of rapamycin (mTOR), in thymic CD4(+)CD25(+)Foxp3(+) nT(reg)-cell development remains elusive. In the present study, we found that the percentage and cell number of thymic CD4(+)CD25(+)Foxp3(+) nT(reg) cells were significantly increased in T-cell-specific TSC1-knockout (TSC1KO) mice. Nevertheless, the levels of CD4(+)CD25(+)Foxp3(-) nT(reg) precursors in TSC1KO thymus were indistinguishable from those in wild-type mice. TSC1KO CD4(+)CD25(+)Foxp3(+) nT(reg) cells showed normal cell death but enhanced proliferative response to IL-2 in a STAT5-dependent manner. Rapamycin (Rapa) treatment failed to rescue but rather increased the frequency of CD4(+)CD25(+)Foxp3(+) nT(reg) cells in TSC1KO and RictorKO mice. The percentage and cell number of thymic CD4(+)CD25(+)Foxp3(+) nT(reg) cells were significantly increased in T-cell-specific RictorKO mice but not in PtenKO mice. Collectively, our studies suggest that TSC1 plays an important role in regulating thymic CD4(+)CD25(+)Foxp3(+) nT(reg)-cell development via a Rapa-resistant and mTORC2-dependent signaling pathway.Chen, H, Zhang, L., Zhang, H., Xiao, Y., Shao, L., Li, H., Yin, H., Wang, R., Liu, G., Corley, D., Yang, Z., Zhao, Y. Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4(+)CD25(+)Foxp3(+) regulatory T-cell development in mice.