Blanco, Daniel BastardoChapman, Nicole M.Raynor, Jana L.Xu, ChengxianSu, WeiAnil, K. C.Li, WeiLim, Seon AhSchattgen, StefanShi, HaoRisch, IsabelSun, YuDhungana, YogeshKim, YunjungWei, JunRankin, SherriNeale, GeoffreyThomas, Paul G.Yang, KaiChi, Hongbo2024-01-032024-01-032022Blanco DB, Chapman NM, Raynor JL, et al. PTEN directs developmental and metabolic signaling for innate-like T cell fate and tissue homeostasis. Nat Cell Biol. 2022;24(11):1642-1654. doi:10.1038/s41556-022-01011-whttps://hdl.handle.net/1805/37559Phosphatase and tensin homologue (PTEN) is frequently mutated in human cancer, but its roles in lymphopoiesis and tissue homeostasis remain poorly defined. Here we show that PTEN orchestrates a two-step developmental process linking antigen receptor and IL-23-Stat3 signalling to type-17 innate-like T cell generation. Loss of PTEN leads to pronounced accumulation of mature IL-17-producing innate-like T cells in the thymus. IL-23 is essential for their accumulation, and ablation of IL-23 or IL-17 signalling rectifies the reduced survival of female PTEN-haploinsufficient mice that model human patients with PTEN mutations. Single-cell transcriptome and network analyses revealed the dynamic regulation of PTEN, mTOR and metabolic activities that accompanied type-17 cell programming. Furthermore, deletion of mTORC1 or mTORC2 blocks PTEN loss-driven type-17 cell accumulation, and this is further shaped by the Foxo1 and Stat3 pathways. Collectively, our study establishes developmental and metabolic signalling networks underpinning type-17 cell fate decisions and their functional effects at coordinating PTEN-dependent tissue homeostasis.en-USPublisher PolicyHomeostasisPTEN PhosphohydrolaseT-LymphocytesInterleukin-17Interleukin-23Article