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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation
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Gene Expression Regulation
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Humans
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Interleukin-15 / genetics
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Interleukin-15 / immunology
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Interleukin-2 Receptor beta Subunit / genetics
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Interleukin-2 Receptor beta Subunit / immunology
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Killer Cells, Natural / cytology
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Killer Cells, Natural / immunology*
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Large Neutral Amino Acid-Transporter 1 / genetics
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Large Neutral Amino Acid-Transporter 1 / immunology
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Lymphocyte Activation
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Rapamycin-Insensitive Companion of mTOR Protein / deficiency
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Rapamycin-Insensitive Companion of mTOR Protein / genetics*
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Rapamycin-Insensitive Companion of mTOR Protein / immunology
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Regulatory-Associated Protein of mTOR / deficiency
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Regulatory-Associated Protein of mTOR / genetics*
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Regulatory-Associated Protein of mTOR / immunology
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / immunology
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Signal Transduction
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T-Box Domain Proteins / genetics*
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T-Box Domain Proteins / immunology
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T-bet Transcription Factor
Substances
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Eomes protein, mouse
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Il2rb protein, mouse
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Interleukin-15
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Interleukin-2 Receptor beta Subunit
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Large Neutral Amino Acid-Transporter 1
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Rapamycin-Insensitive Companion of mTOR Protein
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Regulatory-Associated Protein of mTOR
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Rptor protein, mouse
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STAT5 Transcription Factor
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T-Box Domain Proteins
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T-bet Transcription Factor
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rictor protein, mouse