title: Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4+ CD25+ Foxp3+ regulatory T-cell development in mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Lianjun
authors.initials: L
authors.lastname: Zhang
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiao
authors.forename: Lijuan
authors.initials: L
authors.lastname: Shao
authors.forename: Hongran
authors.initials: H
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Yin
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Wang
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
authors.forename: Douglas
authors.initials: D
authors.lastname: Corley
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D046912:Multiprotein Complexes; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Rictor; mTOR; thymus