Abstract
Foxo transcription factors regulate cell cycle progression, cell survival and DNA-repair pathways. Here we demonstrate that deficiency in Foxo3 resulted in greater expansion of T cell populations after viral infection. This exaggerated expansion was not T cell intrinsic. Instead, it was caused by the enhanced capacity of Foxo3-deficient dendritic cells to sustain T cell viability by producing more interleukin 6. Stimulation of dendritic cells mediated by the coinhibitory molecule CTLA-4 induced nuclear localization of Foxo3, which in turn inhibited the production of interleukin 6 and tumor necrosis factor. Thus, Foxo3 acts to constrain the production of key inflammatory cytokines by dendritic cells and to control T cell survival.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen Presentation / immunology
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Antigens, CD / immunology
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Antigens, CD / metabolism
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Arenaviridae Infections / immunology
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Blotting, Western
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CTLA-4 Antigen
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Flow Cytometry
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Forkhead Box Protein O3
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Forkhead Transcription Factors / immunology*
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Forkhead Transcription Factors / metabolism
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Interleukin-6 / immunology
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Interleukin-6 / metabolism
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Lymphocyte Activation / immunology*
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Lymphocytic choriomeningitis virus / immunology
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Mice
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Mice, Congenic
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Mice, Transgenic
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Protein Transport / immunology
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antigens, CD
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CTLA-4 Antigen
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Ctla4 protein, mouse
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Interleukin-6
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Tumor Necrosis Factor-alpha