title: TSC1 regulates the balance between effector and regulatory T cells.
abstract: Mammalian target of rapamycin (mTOR) plays a crucial role in the control of T cell fate determination; however, the precise regulatory mechanism of the mTOR pathway is not fully understood. We found that T cell-specific deletion of the gene encoding tuberous sclerosis 1 (TSC1), an upstream negative regulator of mTOR, resulted in augmented Th1 and Th17 differentiation and led to severe intestinal inflammation in a colitis model. Conditional Tsc1 deletion in Tregs impaired their suppressive activity and expression of the Treg marker Foxp3 and resulted in increased IL-17 production under inflammatory conditions. A fate-mapping study revealed that Tsc1-null Tregs that lost Foxp3 expression gained a stronger effector-like phenotype compared with Tsc1-/- Foxp3+ Tregs. Elevated IL-17 production in Tsc1-/- Treg cells was reversed by in vivo knockdown of the mTOR target S6K1. Moreover, IL-17 production was enhanced by Treg-specific double deletion of Tsc1 and Foxo3a. Collectively, these studies suggest that TSC1 acts as an important checkpoint for maintaining immune homeostasis by regulating cell fate determination.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Park
authors.forename: Hyung-Seung
authors.initials: HS
authors.lastname: Jin
authors.forename: Justine
authors.initials: J
authors.lastname: Lopez
authors.forename: Chris
authors.initials: C
authors.lastname: Elly
authors.forename: Gisen
authors.initials: G
authors.lastname: Kim
authors.forename: Masako
authors.initials: M
authors.lastname: Murai
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Yun-Cai
authors.initials: YC
authors.lastname: Liu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D011828:Radiation Chimera; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D016207:Cytokines; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse