期刊
PLOS ONE
卷 7, 期 2, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0030592
关键词
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资金
- Ministry of Science and Technology of China [2010CB945301, 2009CB522203]
- National Natural Science Foundation [C81072396, U0832003]
- Chinese Academy of Sciences for Distinguished Young Scientists [KSCX2-EW-Q-7]
The PI3K-Akt-mTOR pathway plays crucial roles in regulating both innate and adaptive immunity. However, the role of TSC1, a critical negative regulator of mTOR, in peripheral T cell homeostasis remains elusive. With T cell-specific Tsc1 conditional knockout (Tsc1 KO) mice, we found that peripheral naive CD8(+) T cells but not CD4(+) T cells were severely reduced. Tsc1 KO naive CD8(+) T cells showed profound survival defect in an adoptive transfer model and in culture with either stimulation of IL-7 or IL-15, despite comparable CD122 and CD127 expression between control and KO CD8(+) T cells. IL-7 stimulated phosphorylation of Akt(S473) was diminished in Tsc1 KO naive CD8(+) T cells due to hyperactive mTOR-mediated feedback suppression on PI3K-AKT signaling. Furthermore, impaired Foxo1/Foxo3a phosphorylation and increased pro-apoptotic Bim expression in Tsc1 KO naive CD8(+) T cells were observed upon stimulation of IL-7. Collectively, our study suggests that TSC1 plays an essential role in regulating peripheral naive CD8(+) T cell homeostasis, possible via an mTOR-Akt-FoxO-Bim signaling pathway.
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