Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA.
Nat Cell Biol. 2022 Nov;24(11):1642-1654. doi: 10.1038/s41556-022-01011-w. Epub 2022 Oct 27.
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.
磷酸酶和张力蛋白同源物（PTEN）在人类癌症中经常发生突变，但它在淋巴发生和组织稳态中的作用仍未得到明确界定。在这里，我们表明 PTEN 协调了一个两步的发育过程，将抗原受体和 IL-23-Stat3 信号与 1 型 17 先天样 T 细胞的产生联系起来。PTEN 的缺失导致成熟的产生 IL-17 的先天样 T 细胞在胸腺中明显积累。IL-23 对于它们的积累是必不可少的，并且消除 IL-23 或 IL-17 信号可以纠正女性 PTEN 半不足小鼠的生存能力降低，这些小鼠模型化了具有 PTEN 突变的人类患者。单细胞转录组和网络分析揭示了伴随 1 型 17 细胞编程的 PTEN、mTOR 和代谢活性的动态调节。此外，删除 mTORC1 或 mTORC2 会阻止由 PTEN 缺失驱动的 1 型 17 细胞积累，而这进一步由 Foxo1 和 Stat3 途径塑造。总的来说，我们的研究确立了 17 型细胞命运决定及其在协调 PTEN 依赖性组织稳态中的功能效应的发育和代谢信号网络。
