Abstract
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 naïve CD8(+) T cells but not CD4(+) T cells were severely reduced. Tsc1 KO naïve 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 naïve 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 naïve CD8(+)T cells were observed upon stimulation of IL-7. Collectively, our study suggests that TSC1 plays an essential role in regulating peripheral naïve CD8(+) T cell homeostasis, possible via an mTOR-Akt-FoxO-Bim signaling pathway.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adoptive Transfer
-
Animals
-
CD4-Positive T-Lymphocytes / cytology
-
CD4-Positive T-Lymphocytes / drug effects
-
CD4-Positive T-Lymphocytes / immunology
-
CD8-Positive T-Lymphocytes / cytology*
-
CD8-Positive T-Lymphocytes / drug effects
-
CD8-Positive T-Lymphocytes / immunology*
-
Cell Survival / immunology
-
Forkhead Box Protein O1
-
Forkhead Box Protein O3
-
Forkhead Transcription Factors / metabolism
-
Homeostasis / drug effects
-
Homeostasis / immunology*
-
Interleukin-15 / pharmacology
-
Interleukin-7 / pharmacology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Models, Animal
-
Models, Immunological
-
Organ Specificity / drug effects
-
Organ Specificity / immunology
-
Phosphorylation / drug effects
-
Proto-Oncogene Proteins c-akt / metabolism
-
Signal Transduction / drug effects
-
Signal Transduction / immunology*
-
Sirolimus / pharmacology
-
Tuberous Sclerosis Complex 1 Protein
-
Tuberous Sclerosis Complex 2 Protein
-
Tumor Suppressor Proteins / metabolism*
Substances
-
Forkhead Box Protein O1
-
Forkhead Box Protein O3
-
Forkhead Transcription Factors
-
FoxO3 protein, mouse
-
Foxo1 protein, mouse
-
Interleukin-15
-
Interleukin-7
-
Tsc1 protein, mouse
-
Tuberous Sclerosis Complex 1 Protein
-
Tuberous Sclerosis Complex 2 Protein
-
Tumor Suppressor Proteins
-
Proto-Oncogene Proteins c-akt
-
Sirolimus