PMID- 31433805
OWN - NLM
STAT- MEDLINE
DCOM- 20200227
LR  - 20211204
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 17
IP  - 8
DP  - 2019 Aug
TI  - TSC1/mTOR-controlled metabolic-epigenetic cross talk underpins DC control of CD8+ 
      T-cell homeostasis.
PG  - e3000420
LID - 10.1371/journal.pbio.3000420 [doi]
LID - e3000420
AB  - Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, 
      and metabolic programing has been recently linked to DC development and function. 
      However, the metabolic underpinnings corresponding to distinct DC functions 
      remain largely unresolved. Here, we demonstrate a special metabolic-epigenetic 
      coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 
      (TSC1)-mechanistic target of rapamycin (mTOR) for homeostatic DC function. 
      Specific ablation of Tsc1 in the DC compartment (Tsc1DC-KO) largely preserved DC 
      development but led to pronounced reduction in naive and memory-phenotype cluster 
      of differentiation (CD)8+ T cells, a defect fully rescued by concomitant ablation 
      of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) in DCs. 
      Moreover, Tsc1DC-KO mice were unable to launch efficient antigen-specific CD8+ T 
      effector responses required for containing Listeria monocytogenes and B16 
      melanomas. Mechanistically, our data suggest that the steady-state DCs tend to 
      tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) 
      for histone acetylation, a process critically controlled by TSC1-mTOR. 
      Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) 
      expression and fatty acid synthesis, leading to impaired epigenetic imprinting on 
      selective genes such as major histocompatibility complex (MHC)-I and interleukin 
      (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic 
      acetyl-CoA for histone acetylation and restore the gene expression program 
      compromised by TSC1 deficiency. Taken together, our results uncover a crucial 
      role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell 
      homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm 
      for DC specification.
FAU - Shi, Lei
AU  - Shi L
AD  - School of Life Sciences, Lanzhou University, Lanzhou, Gansu, China.
AD  - CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of 
      Shanghai; CAS Center for Excellence in Molecular Cell Science; University of 
      Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Chen, Xia
AU  - Chen X
AD  - School of Life Sciences, Lanzhou University, Lanzhou, Gansu, China.
AD  - CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of 
      Shanghai; CAS Center for Excellence in Molecular Cell Science; University of 
      Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Zang, Aiping
AU  - Zang A
AD  - CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of 
      Shanghai; CAS Center for Excellence in Molecular Cell Science; University of 
      Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Li, Tiantian
AU  - Li T
AD  - CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of 
      Shanghai; CAS Center for Excellence in Molecular Cell Science; University of 
      Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Hu, Yanxiang
AU  - Hu Y
AD  - Department of Immunology, Medical College of Qingdao University, Qingdao, 
      Shandong, China.
FAU - Ma, Shixin
AU  - Ma S
AD  - CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of 
      Shanghai; CAS Center for Excellence in Molecular Cell Science; University of 
      Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Lu, Mengdie
AU  - Lu M
AD  - Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State 
      Key Laboratory of Respiratory Diseases, Guangzhou, Guangdong, China.
FAU - Yin, Huiyong
AU  - Yin H
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
FAU - Wang, Haikun
AU  - Wang H
AD  - CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of 
      Shanghai; CAS Center for Excellence in Molecular Cell Science; University of 
      Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Zhang, Xiaoming
AU  - Zhang X
AD  - CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of 
      Shanghai; CAS Center for Excellence in Molecular Cell Science; University of 
      Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FAU - Zhang, Bei
AU  - Zhang B
AD  - Department of Immunology, Medical College of Qingdao University, Qingdao, 
      Shandong, China.
FAU - Leng, Qibin
AU  - Leng Q
AUID- ORCID: 0000-0002-4768-1312
AD  - Affiliated Cancer Hospital and Institute of Guangzhou Medical University, State 
      Key Laboratory of Respiratory Diseases, Guangzhou, Guangdong, China.
FAU - Yang, Jinbo
AU  - Yang J
AD  - School of Life Sciences, Lanzhou University, Lanzhou, Gansu, China.
FAU - Xiao, Hui
AU  - Xiao H
AUID- ORCID: 0000-0001-5304-243X
AD  - CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of 
      Shanghai; CAS Center for Excellence in Molecular Cell Science; University of 
      Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190821
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (Antigens)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antigens/metabolism
MH  - CD8-Positive T-Lymphocytes/immunology/*metabolism
MH  - Cell Differentiation/physiology
MH  - Dendritic Cells/immunology/*metabolism
MH  - Epigenesis, Genetic
MH  - Homeostasis
MH  - Listeria monocytogenes
MH  - Lymphocyte Activation
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - TOR Serine-Threonine Kinases/genetics/immunology/*metabolism
MH  - Tuberous Sclerosis Complex 1 Protein/genetics/immunology/*metabolism
MH  - Tumor Suppressor Proteins/genetics
PMC - PMC6719877
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/08/23 06:00
MHDA- 2020/02/28 06:00
PMCR- 2019/08/21
CRDT- 2019/08/22 06:00
PHST- 2019/02/28 00:00 [received]
PHST- 2019/08/01 00:00 [accepted]
PHST- 2019/09/03 00:00 [revised]
PHST- 2019/08/23 06:00 [pubmed]
PHST- 2020/02/28 06:00 [medline]
PHST- 2019/08/22 06:00 [entrez]
PHST- 2019/08/21 00:00 [pmc-release]
AID - PBIOLOGY-D-19-00578 [pii]
AID - 10.1371/journal.pbio.3000420 [doi]
PST - epublish
SO  - PLoS Biol. 2019 Aug 21;17(8):e3000420. doi: 10.1371/journal.pbio.3000420. 
      eCollection 2019 Aug.