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Browsing by Author "Lim, Seon Ah"
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Item PTEN directs developmental and metabolic signaling for innate-like T cell fate and tissue homeostasis(Springer Nature, 2022) Blanco, Daniel Bastardo; Chapman, Nicole M.; Raynor, Jana L.; Xu, Chengxian; Su, Wei; Anil, K. C.; Li, Wei; Lim, Seon Ah; Schattgen, Stefan; Shi, Hao; Risch, Isabel; Sun, Yu; Dhungana, Yogesh; Kim, Yunjung; Wei, Jun; Rankin, Sherri; Neale, Geoffrey; Thomas, Paul G.; Yang, Kai; Chi, Hongbo; Pediatrics, School of MedicinePhosphatase 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.