PMID- 25271321
OWN - NLM
STAT- MEDLINE
DCOM- 20150430
LR  - 20211203
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 111
IP  - 41
DP  - 2014 Oct 14
TI  - Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the 
      transcriptional and metabolic programs.
PG  - 14858-63
LID - 10.1073/pnas.1404264111 [doi]
AB  - Memory CD8(+) T cells are an essential component of protective immunity. 
      Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the 
      regulation of the differentiation of effector and memory T cells. However, little 
      is understood about the mechanisms that control mTOR activity, or the effector 
      pathways regulated by mTOR. We describe here that tuberous sclerosis 1 (Tsc1), a 
      regulator of mTOR signaling, plays a crucial role in promoting the 
      differentiation and function of memory CD8(+) T cells in response to Listeria 
      monocytogenes infection. Mice with specific deletion of Tsc1 in 
      antigen-experienced CD8(+) T cells evoked normal effector responses, but were 
      markedly impaired in the generation of memory T cells and their recall responses 
      to antigen reexposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the 
      generation of memory-precursor effector cells while promoting short-lived 
      effector cell differentiation. Transcriptome analysis indicated that Tsc1 
      coordinated gene expression programs underlying immune function, transcriptional 
      regulation, and cell metabolism. Furthermore, Tsc1 deletion led to excessive 
      mTORC1 activity and dysregulated glycolytic and oxidative metabolism in response 
      to IL-15 stimulation. These findings establish a Tsc1-mediated checkpoint in 
      linking immune signaling and cell metabolism to orchestrate memory CD8(+) T-cell 
      development and function.
FAU - Shrestha, Sharad
AU  - Shrestha S
AD  - Department of Immunology and Integrated Biomedical Sciences Program, University 
      of Tennessee Health Science Center, Memphis, TN 38163.
FAU - Yang, Kai
AU  - Yang K
AD  - Department of Immunology and.
FAU - Wei, Jun
AU  - Wei J
AD  - Department of Immunology and.
FAU - Karmaus, Peer W F
AU  - Karmaus PW
AD  - Department of Immunology and.
FAU - Neale, Geoffrey
AU  - Neale G
AD  - Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's 
      Research Hospital, Memphis, TN 38105; and.
FAU - Chi, Hongbo
AU  - Chi H
AD  - Department of Immunology and Integrated Biomedical Sciences Program, University 
      of Tennessee Health Science Center, Memphis, TN 38163 hongbo.chi@stjude.org.
LA  - eng
SI  - GEO/GSE61591
GR  - CA176624/CA/NCI NIH HHS/United States
GR  - AI105887/AI/NIAID NIH HHS/United States
GR  - AI101407/AI/NIAID NIH HHS/United States
GR  - NS064599/NS/NINDS NIH HHS/United States
GR  - R01 NS064599/NS/NINDS NIH HHS/United States
GR  - P30 CA021765/CA/NCI NIH HHS/United States
GR  - R01 AI105887/AI/NIAID NIH HHS/United States
GR  - R01 CA176624/CA/NCI NIH HHS/United States
GR  - R01 AI101407/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140930
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antigens)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antigens/immunology
MH  - CD8-Positive T-Lymphocytes/*cytology/*metabolism
MH  - Cell Differentiation/genetics/*immunology
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation
MH  - Immunologic Memory/*genetics
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice, Inbred C57BL
MH  - Multiprotein Complexes/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Transcription, Genetic
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tumor Suppressor Proteins/deficiency/*metabolism
PMC - PMC4205612
OTO - NOTNLM
OT  - T-cell memory
OT  - glycolysis
OT  - immune response
OT  - oxidative phosphorylation
COIS- The authors declare no conflict of interest.
EDAT- 2014/10/02 06:00
MHDA- 2015/05/01 06:00
PMCR- 2015/04/14
CRDT- 2014/10/02 06:00
PHST- 2014/10/02 06:00 [entrez]
PHST- 2014/10/02 06:00 [pubmed]
PHST- 2015/05/01 06:00 [medline]
PHST- 2015/04/14 00:00 [pmc-release]
AID - 1404264111 [pii]
AID - 201404264 [pii]
AID - 10.1073/pnas.1404264111 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14858-63. doi: 
      10.1073/pnas.1404264111. Epub 2014 Sep 30.