NK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation.
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.
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.|Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
Meixiang
M
Yang
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
Shasha
S
Chen
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
Juan
J
Du
Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
Junming
J
He
Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
Yuande
Y
Wang
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
Zehua
Z
Li
Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
Guangao
G
Liu
Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
Wanwen
W
Peng
Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China.
Xiaokang
X
Zeng
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
Dan
D
Li
School of Medicine, Tsinghua University, Beijing 100086, China.
Panglian
P
Xu
School of Medicine, Tsinghua University, Beijing 100086, China.
Wei
W
Guo
Center of Animal Facility, Tsinghua University, Beijing 100086, China.
Zai
Z
Chang
Collaborative Innovation Center, Wuhan Sports University, Wuhan 340036, China.
Song
S
Wang
School of Life Sciences, University of Sciences and Technology of China, Hefei 230026, China.
Zhigang
Z
Tian
Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100086, China.
Zhongjun
Z
Dong
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes; D005786:Gene Expression Regulation / Q000502:physiology; D006410:Hematopoiesis / Q000502:physiology; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000235:genetics / Q000378:metabolism*; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D021122:Protein Subunits; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
C491198:Eomes protein, mouse; C508022:Il2rb protein, mouse; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; D021122:Protein Subunits; D020825:T-Box Domain Proteins; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1