PTEN directs developmental and metabolic signaling for innate-like T cell fate and tissue homeostasis

Daniel Bastardo Blanco, Nicole M. Chapman, Jana L. Raynor, Chengxian Xu, Wei Su, Anil Kc, Wei Li, Seon Ah Lim, Stefan Schattgen, Hao Shi, Isabel Risch, Yu Sun, Yogesh Dhungana, Yunjung Kim, Jun Wei, Sherri Rankin, Geoffrey Neale, Paul G. Thomas, Kai Yang, Hongbo Chi

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Phosphatase 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.

Original languageEnglish
Pages (from-to)1642-1654
Number of pages13
JournalNature Cell Biology
Volume24
Issue number11
DOIs
StatePublished - Nov 2022

Bibliographical note

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© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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