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mTORC1 和 mTORC2 之间的串扰改变细胞因子信号转导以控制 NK 细胞成熟和效应功能。

Crosstalks between mTORC1 and mTORC2 variagate cytokine signaling to control NK maturation and effector function.

机构信息

Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), 30# Gaotanyan Road, Shapingba District, Chongqing, 400038, China.

Department of Laboratory Medicine, PLA 307 Hospital, Dongdajie 8, Fengtai District, Beijing, 100071, China.

出版信息

Nat Commun. 2018 Nov 19;9(1):4874. doi: 10.1038/s41467-018-07277-9.

DOI:10.1038/s41467-018-07277-9
PMID:30451838
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6242843/
Abstract

The metabolic checkpoint kinase mechanistic/mammalian target of rapamycin (mTOR) regulates natural killer (NK) cell development and function, but the exact underlying mechanisms remain unclear. Here, we show, via conditional deletion of Raptor (mTORC1) or Rictor (mTORC2), that mTORC1 and mTORC2 promote NK cell maturation in a cooperative and non-redundant manner, mainly by controlling the expression of Tbx21 and Eomes. Intriguingly, mTORC1 and mTORC2 regulate cytolytic function in an opposing way, exhibiting promoting and inhibitory effects on the anti-tumor ability and metabolism, respectively. mTORC1 sustains mTORC2 activity by maintaining CD122-mediated IL-15 signaling, whereas mTORC2 represses mTORC1-modulated NK cell effector functions by restraining STAT5-mediated SLC7A5 expression. These positive and negative crosstalks between mTORC1 and mTORC2 signaling thus variegate the magnitudes and kinetics of NK cell activation, and help define a paradigm for the modulation of NK maturation and effector functions.

摘要

代谢检查点激酶机制/雷帕霉素靶蛋白（mTOR）调节自然杀伤（NK）细胞的发育和功能，但确切的潜在机制仍不清楚。在这里，我们通过条件性删除 Raptor（mTORC1）或 Rictor（mTORC2）表明，mTORC1 和 mTORC2 以协作且非冗余的方式促进 NK 细胞成熟，主要通过控制 Tbx21 和 Eomes 的表达。有趣的是，mTORC1 和 mTORC2 以相反的方式调节细胞溶解功能，分别对肿瘤杀伤能力和代谢表现出促进和抑制作用。mTORC1 通过维持 CD122 介导的 IL-15 信号来维持 mTORC2 的活性，而 mTORC2 通过抑制 STAT5 介导的 SLC7A5 表达来抑制 mTORC1 调节的 NK 细胞效应功能。因此，mTORC1 和 mTORC2 信号之间的这种正负相互作用改变了 NK 细胞激活的幅度和动力学，并为调节 NK 成熟和效应功能提供了范例。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/b25f55cbbf67/41467_2018_7277_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/701a6ecd6adb/41467_2018_7277_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/c822ffd90d94/41467_2018_7277_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/d930da1ebe7f/41467_2018_7277_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/31f4915a516b/41467_2018_7277_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/c25fd0e39bde/41467_2018_7277_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/45acaa5ecc8b/41467_2018_7277_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/b25f55cbbf67/41467_2018_7277_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/701a6ecd6adb/41467_2018_7277_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/c822ffd90d94/41467_2018_7277_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/d930da1ebe7f/41467_2018_7277_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/31f4915a516b/41467_2018_7277_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/c25fd0e39bde/41467_2018_7277_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/45acaa5ecc8b/41467_2018_7277_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2921/6242843/b25f55cbbf67/41467_2018_7277_Fig7_HTML.jpg

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Acta Pharmacol Sin. 2025 Feb 25. doi: 10.1038/s41401-025-01497-8.
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