Document Detail


Tumor suppressor TSC1 is critical for T-cell anergy.
MedLine Citation:
PMID:  22891340     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
T-cell anergy is a state of T cells that is hyporesponsive to stimulation via the T-cell receptor and costimulatory molecules and is thought to be important for self-tolerance. How T-cell anergy is regulated is still poorly understood. We report here that tuberous sclerosis (TSC)1 is critical for T-cell anergy. Deficiency of TSC1 resulted in enhanced T-cell proliferation and cytokine production in the absence of cluster of differentiation (CD)28-mediated costimulation, accompanied by enhanced T-cell metabolism. Resistance of TSC1-deficient T cells to anergy is correlated with increased signaling through the mammalian target of rapamycin complex (mTORC)1 and can be reverted by treatment of these cells with mTORC1 inhibitor rapamycin. Expression of the inducible costimulator (ICOS) is increased in TSC1-deficient T cells, which can be inhibited by rapamycin. Simultaneous blockade of both CD28 and ICOS costimulation partially restored sensitivity of TSC1-deficient T cells to anergy induction. Together, our data indicate that TSC1 is crucial for T-cell anergy by inhibiting mTORC1 signaling through both ICOS-dependent and -independent mechanisms.
Authors:
Dan-Li Xie; Jinhong Wu; Yong-Liang Lou; Xiao-Ping Zhong
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-13
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-29     Completed Date:  2012-12-11     Revised Date:  2013-09-30    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  14152-7     Citation Subset:  IM    
Affiliation:
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD28 / immunology,  metabolism
Cell Division / immunology
Clonal Anergy / immunology*
Energy Metabolism / immunology
Immune Tolerance / immunology
Inducible T-Cell Co-Stimulator Protein / immunology,  metabolism
Lymphocyte Activation / immunology
Mice
Mice, Knockout
Proteins / immunology,  metabolism
Signal Transduction / immunology
T-Lymphocytes / cytology*,  immunology*,  metabolism
Tumor Suppressor Proteins / genetics,  immunology*,  metabolism
Grant Support
ID/Acronym/Agency:
AI076357/AI/NIAID NIH HHS; AI079088/AI/NIAID NIH HHS; AI101206/AI/NIAID NIH HHS; R01 AI076357/AI/NIAID NIH HHS; R01 AI079088/AI/NIAID NIH HHS; R01 AI101206/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD28; 0/Icos protein, mouse; 0/Inducible T-Cell Co-Stimulator Protein; 0/Proteins; 0/Tumor Suppressor Proteins; 0/mechanistic target of rapamycin complex 1; 0/tuberous sclerosis complex 1 protein
Comments/Corrections

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