Abstract
Natural killer (NK) cell development is a multistep process that requires a variety of signals and transcription factors. The lack of mammalian target of rapamycin (mTOR) kinase severely impairs NK cell development in mice. mTOR binds to Raptor and Rictor to form two complexes, mTORC1 and mTORC2, respectively. How mTOR and its two complexes regulate NK cell development is not fully understood. Here, we developed two methods to inactivate mTOR, Raptor, or Rictor in early stage NK cells (using CD122-Cre) or in late-stage NK cells (using Ncr1-CreTg). First, we found that when mTOR was deleted by CD122-Cre during and after NK cell commitment, NK cell development was severely impaired, while Ncr1-CreTg mediated mTOR deletion slightly affected NK cell terminal differentiation, suggesting that mTOR is essential for early NK cell differentiation. Second, we found that CD122-mediated deletion of Raptor significantly limited the differentiation of CD27+CD11b− immature NK (iNK) cell into mature NK cells. In contrast, the absence of Rictor significantly interfered with the differentiation of CD27−CD11b− early iNK cells. Third, Ncr1-mediated deletion of Raptor, rather than Rictor, moderately affected NK cell terminal differentiation. In terms of mechanism, mTORC1 mainly promotes the expression of NK cell-specific transcription factor E4 promoter-binding protein 4 (E4BP4), while both mTORC1 and mTORC2 can enhance the expression of T-bet. Therefore, mTORC1 and mTORC2 subtly coordinate NK cell development by differentially inducing E4BP4 and T-bet.
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Funding
Research reported in this publication was supported by the Natural Science Foundation of China (to ZD, 81725007, 31830027, 31821003, and 91942308; to MY, 81771666, and 81471523; to WX, 31700771), National Key Research & Developmental Program of China (to ZD, 2018YFC1003900), Natural Science Foundation of Guangdong Province (to MY, 2019A1515011707), Guangzhou Science and Technology Project (to MY, 201707010395), and by 111 Project (B16201).
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DL and YW performed and analyzed experiments; DL, MY, and ZD designed experiments, analyzed data, and wrote the paper.
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Li, D., Wang, Y., Yang, M. et al. mTORC1 and mTORC2 coordinate early NK cell development by differentially inducing E4BP4 and T-bet. Cell Death Differ 28, 1900–1909 (2021). https://doi.org/10.1038/s41418-020-00715-6
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DOI: https://doi.org/10.1038/s41418-020-00715-6
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