Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, United States.
Departments of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, United States.
Elife. 2018 May 29;7:e35619. doi: 10.7554/eLife.35619.
Natural killer (NK) cells are innate lymphoid cells that are essential for innate and adaptive immunity. Mechanistic target of rapamycin (mTOR) is critical for NK cell development; however, the independent roles of mTORC1 or mTORC2 in regulating this process remain unknown. -mediated deletion of or in mice results in altered homeostatic NK cellularity and impaired development at distinct stages. The transition from the CD27CD11b to the CD27CD11b stage is impaired in cKO mice, while, the terminal maturation from the CD27CD11b to the CD27CD11b stage is compromised in cKO mice. Mechanistically, Raptor-deficiency renders substantial alteration of the gene expression profile including transcription factors governing early NK cell development. Comparatively, loss of Rictor causes more restricted transcriptome changes. The reduced expression of T-bet correlates with the terminal maturation defects and results from impaired mTORC2-Akt-FoxO1 signaling. Collectively, our results reveal the divergent roles of mTORC1 and mTORC2 in NK cell development.
自然杀伤 (NK) 细胞是先天淋巴细胞，对于先天免疫和适应性免疫至关重要。雷帕霉素靶蛋白 (mTOR) 是 NK 细胞发育的关键；然而，mTORC1 或 mTORC2 在调节这一过程中的独立作用尚不清楚。在小鼠中，通过 或 介导的缺失导致稳态 NK 细胞数量发生改变，并在不同阶段发育受损。在 cKO 小鼠中，从 CD27CD11b 到 CD27CD11b 阶段的转变受损，而在 cKO 小鼠中，从 CD27CD11b 到 CD27CD11b 阶段的终末成熟受损。从机制上讲，Raptor 的缺失导致包括控制早期 NK 细胞发育的转录因子在内的基因表达谱发生重大改变。相比之下，Rictor 的缺失导致转录组变化更受限制。T-bet 的表达减少与终末成熟缺陷相关，并且源自受损的 mTORC2-Akt-FoxO1 信号传导。总之，我们的结果揭示了 mTORC1 和 mTORC2 在 NK 细胞发育中的不同作用。
