Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4+CD25+Foxp3+, regulatory T-cell development in mice

被引：39

作者：

Chen, Hui ^{[1
]}

Zhang, Lianjun ^{[1
]}

Zhang, Hongbing ^{[2
,3
,4
]}

Xiao, Yi ^{[1
]}

Shao, Lijuan ^{[5
]}

Li, Hongran ^{[1
]}

Yin, Hui ^{[1
]}

Wang, Ruoyu ^{[5
]}

Liu, Guangwei ^{[1
]}

Corley, Douglas ^{[1
]}

Yang, Zhongzhou ^{[6
]}

Zhao, Yong ^{[1
]}

机构：

[1] Chinese Acad Sci, Inst Zool, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100101, Peoples R China

[2] Chinese Acad Med Sci, Inst Basic Med Sci, Dept Physiol & Pathophysiol, Natl Lab Med Mol Biol, Beijing 100730, Peoples R China

[3] Chinese Acad Med Sci, Sch Basic Med, Beijing 100730, Peoples R China

[4] Peking Union Med Coll, Beijing 100021, Peoples R China

[5] Dalian Univ, Dept Oncol, Affiliated Zhongshan Hosp, Dalian 116012, Peoples R China

[6] Nanjing Univ, Minist Educ Key Lab Model Anim Dis Study, Model Anim Res Ctr, Nanjing 210008, Jiangsu, Peoples R China

来源：

FASEB JOURNAL | 2013年 / 27卷 / 10期

关键词：

mTOR; thymus; Rictor; TUMOR-SUPPRESSOR TSC1; MAMMALIAN TARGET; RAPAMYCIN; MTOR; DIFFERENTIATION; CYCLOSPORINE; QUIESCENCE; EXPRESSION; MAINTAINS; SURVIVAL;

D O I：

10.1096/fj.13-235408

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：3979 / 3990

页数：12

共 47 条

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Helios Expression Is a Marker of T Cell Activation and Proliferation [J].