Abstract
Dendritic cell (DC) maturation is characterized by upregulation of cell-surface MHC class II (MHC-II) and costimulatory molecules, and production of a variety of cytokines that can shape both innate and adaptive immunity. Paradoxically, transcription of the MHC-II genes, as well as its activator, CIITA, is rapidly silenced during DC maturation. The mechanisms that control CIITA/MHC-II expression and silencing have not been fully understood. We report in this article that the tumor suppressor tuberous sclerosis complex 1 (TSC1) is a critical regulator of DC function for both innate and adaptive immunity. Its deficiency in DCs results in increased mammalian target of rapamycin (mTOR) complex 1 but decreased mTORC2 signaling, altered cytokine production, impaired CIITA/MHC-II expression, and defective Ag presentation to CD4 T cells after TLR4 stimulation. We demonstrate further that IFN regulatory factor 4 can directly bind to CIITA promoters, and decreased IFN regulatory factor 4 expression is partially responsible for decreased CIITA/MHC-II expression in TSC1-deficient DCs. Moreover, we identify that CIITA/MHC-II silencing during DC maturation requires mTOR complex 1 activity. Together, our data reveal unexpected roles of TSC1/mTOR that control multifaceted functions of DCs.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigen Presentation / immunology
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Bone Marrow Cells / metabolism
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation
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Cells, Cultured
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Histocompatibility Antigens Class II / immunology
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Interferon Regulatory Factors / metabolism*
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Lymphocyte Activation
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Multiprotein Complexes / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Promoter Regions, Genetic
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Proteins / metabolism
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RNA Interference
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RNA, Small Interfering
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Signal Transduction / immunology
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TOR Serine-Threonine Kinases / metabolism
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Toll-Like Receptor 4 / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Tuberous Sclerosis Complex 1 Protein
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Tumor Suppressor Proteins / metabolism*
Substances
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Histocompatibility Antigens Class II
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Interferon Regulatory Factors
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MHC class II transactivator protein
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Multiprotein Complexes
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Nuclear Proteins
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Proteins
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RNA, Small Interfering
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Trans-Activators
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Tsc1 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tumor Suppressor Proteins
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interferon regulatory factor-4
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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TOR Serine-Threonine Kinases