NK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation
Open accessAbstract
Activation of metabolic signalling by IL-15 is required for natural killer (NK) cell development. Here we show that Tsc1, a repressor of mTOR, is dispensable for the terminal maturation, survival and function of NK cells but is critical to restrict exhaustive proliferation of immature NK cells and activation downstream of IL-15 during NK cell development. Tsc1 is expressed in immature NK cells and is upregulated by IL-15. Haematopoietic-specific deletion of Tsc1 causes a marked decrease in the number of NK cells and compromises rejection of ‘missing-self’ haematopoietic tumours and allogeneic bone marrow. The residual Tsc1-null NK cells display activated, pro-apoptotic phenotype and elevated mTORC1 activity. Deletion of Raptor, a component of mTORC1, largely reverses these defects. Tsc1-deficient NK cells express increased levels of T-bet and downregulate Eomes and CD122, a subunit of IL-15 receptor. These results reveal a role for Tsc1-dependent inhibition of mTORC1 activation during immature NK cell development.
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The tuberous sclerosis tumor suppressor complex, composed of TSC1 and TSC2, negatively regulates mTORC1 activity.
“The tuberous sclerosis tumor suppressor complex (TSC), composed of TSC1 and TSC2, negatively regulates mTORC1 activity (Yang et al., 2016).”
From Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells (2017) · cites this paper as Yang et al., 2016
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Self-citation
- Authors
- Yang, M., Chen, S., Du, J., He, J., Wang, Y., Li, Z., Liu, G., Peng, W., Zeng, X., Li, D., Xu, P., Guo, W., Chang, Z., Wang, S., Tian, Z., & Dong, Z.
- Affiliations
- Jinan University (CN)
- Tsinghua University (CN)
- Wuhan Sports University (CN)
- University of Science and Technology of China (CN)
- Corresponding author
- Dong, Zhongjun
- ORCID
- Venue
- Nature Communications
- Published
- 2016-09-07
- Volume
- 7
- Issue
- 1
- Pages
- 12730-12730
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5023956
- OpenAlex
- W2515467040
- Cited by
- 73
- References
- 42
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 8 · 2023: 6 · 2022: 4 · 2021: 20 · 2020: 10 · 2019: 7 · 2018: 7 · 2017: 4
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81361128016, 81273198, 81322041, 81471523, 91429303, 2013CB944901)
- Tsinghua University
- Peking Union Medical College
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- NK cell development, TSC1, mTORC1, raptors, NK cell exhaustion, metabolic signalling, T-bet, Eomes, CD122, NK cell apoptosis
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 1 Protein, Animals, B-Lymphocytes, Gene Expression Regulation, Hematopoiesis, Killer Cells, Natural, Melanoma, Experimental, T-Lymphocytes, Up-Regulation, Apoptosis, Mice, Knockout, Interleukin-15, T-Box Domain Proteins, Protein Subunits, Tumor Suppressor Proteins, Mice, Interleukin-2 Receptor beta Subunit
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