title: TSC1/2 signaling complex is essential for peripheral naïve CD8+ T cell survival and homeostasis in mice.
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.
authors.affiliation: Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Lianjun
authors.initials: L
authors.lastname: Zhang
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.forename: Lanlan
authors.initials: L
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiao
authors.forename: Enyu
authors.initials: E
authors.lastname: Rao
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Miao
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Lina
authors.initials: L
authors.lastname: Sun
authors.forename: Hongran
authors.initials: H
authors.lastname: Li
authors.forename: Guangwei
authors.initials: G
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D019409:Interleukin-15 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D018448:Models, Immunological; D009928:Organ Specificity / Q000187:drug effects / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D019409:Interleukin-15; D015851:Interleukin-7; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus