美国圣犹大儿童研究医院迟洪波研究组发现，磷酸酶和紧张素同源物(PTEN)指导先天样T细胞命运和组织稳态的发育和代谢信号。相关论文于2022年10月27日发表在《自然—细胞生物学》杂志上。

本研究显示，PTEN协调了抗原受体和IL-23-Stat3信号通路与17型先天样T细胞生成之间的两步发育过程。PTEN的缺失导致胸腺中产生IL-17的成熟的先天性T细胞的明显积累。IL-23对它们的积累至关重要，而IL-23或IL-17消耗信号可以纠正PTEN突变的人类患者模型中，雌性PTEN单倍不足小鼠下降的存活率。

单细胞转录组和网络分析揭示了伴随17型细胞编程的PTEN、mTOR和代谢活性的动态调控。此外，mTORC1或mTORC2的缺失阻断了PTEN损失驱动的17型细胞积累，这进一步受到Foxo1和Stat3通路的影响。总之，他们的研究建立了发育和代谢信号网络，支持17型细胞命运决定及其协调PTEN依赖的组织稳态的功能效应。

据了解，PTEN在人类癌症中经常发生突变，但其在淋巴系统和组织稳态中的作用尚不明确。

附：英文原文

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

Author: Blanco, Daniel Bastardo, Chapman, Nicole M., Raynor, Jana L., Xu, Chengxian, Su, Wei, KC, Anil, 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

Issue&Volume: 2022-10-27

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.

DOI: 10.1038/s41556-022-01011-w

Source: https://www.nature.com/articles/s41556-022-01011-w