PMID- 23882125
OWN - NLM
STAT- MEDLINE
DCOM- 20131216
LR  - 20211203
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 27
IP  - 10
DP  - 2013 Oct
TI  - Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4+ 
      CD25+ Foxp3+ regulatory T-cell development in mice.
PG  - 3979-90
LID - 10.1096/fj.13-235408 [doi]
AB  - Thymic-derived CD4(+)CD25(+)Foxp3(+) natural regulatory T (nTreg) cells are 
      essential for the maintenance of peripheral immune tolerance. Signaling pathways 
      that drive immature thymic progenitors to differentiate into 
      CD4(+)CD25(+)Foxp3(+) nTreg 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(+) nTreg-cell development remains elusive. 
      In the present study, we found that the percentage and cell number of thymic 
      CD4(+)CD25(+)Foxp3(+) nTreg cells were significantly increased in T-cell-specific 
      TSC1-knockout (TSC1KO) mice. Nevertheless, the levels of CD4(+)CD25(+)Foxp3(-) 
      nTreg precursors in TSC1KO thymus were indistinguishable from those in wild-type 
      mice. TSC1KO CD4(+)CD25(+)Foxp3(+) nTreg 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(+) nTreg cells in TSC1KO and RictorKO mice. The percentage and 
      cell number of thymic CD4(+)CD25(+)Foxp3(+) nTreg 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(+) nTreg-cell development via a Rapa-resistant and 
      mTORC2-dependent signaling pathway.
FAU - Chen, Hui
AU  - Chen H
AD  - 2Y.Z., Transplantation Biology Research Division, State Key Laboratory of 
      Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of 
      Sciences, Beichen West Rd. 1-5, Chaoyang District, Beijing, China 100101. 
      zhaoy@ioz.ac.cn.
FAU - Zhang, Lianjun
AU  - Zhang L
FAU - Zhang, Hongbing
AU  - Zhang H
FAU - Xiao, Yi
AU  - Xiao Y
FAU - Shao, Lijuan
AU  - Shao L
FAU - Li, Hongran
AU  - Li H
FAU - Yin, Hui
AU  - Yin H
FAU - Wang, Ruoyu
AU  - Wang R
FAU - Liu, Guangwei
AU  - Liu G
FAU - Corley, Douglas
AU  - Corley D
FAU - Yang, Zhongzhou
AU  - Yang Z
FAU - Zhao, Yong
AU  - Zhao Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130723
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (CD4 Antigens)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, mouse)
RN  - 0 (Interleukin-2 Receptor alpha Subunit)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - CD4 Antigens/genetics/*metabolism
MH  - Forkhead Transcription Factors/genetics/*metabolism
MH  - Interleukin-2 Receptor alpha Subunit/genetics/*metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Knockout
MH  - Multiprotein Complexes/genetics/metabolism
MH  - Signal Transduction/*physiology
MH  - T-Lymphocytes, Regulatory/physiology
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
MH  - Thymus Gland/metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/genetics/*metabolism
OTO - NOTNLM
OT  - Rictor
OT  - mTOR
OT  - thymus
EDAT- 2013/07/25 06:00
MHDA- 2013/12/18 06:00
CRDT- 2013/07/25 06:00
PHST- 2013/07/25 06:00 [entrez]
PHST- 2013/07/25 06:00 [pubmed]
PHST- 2013/12/18 06:00 [medline]
AID - fj.13-235408 [pii]
AID - 10.1096/fj.13-235408 [doi]
PST - ppublish
SO  - FASEB J. 2013 Oct;27(10):3979-90. doi: 10.1096/fj.13-235408. Epub 2013 Jul 23.