Abstract
Despite expression of the high-affinity IL-2R, CD4(+)CD25(+) regulatory T cells (Tregs) are hypoproliferative upon IL-2R stimulation in vitro. However the mechanisms by which CD4(+)CD25(+) T cells respond to IL-2 signals are undefined. In this report, we examine the cellular and molecular responses of CD4(+)CD25(+) Tregs to IL-2. IL-2R stimulation results in a G(1) cell cycle arrest, cellular enlargement and increased cellular survival of CD4(+)CD25(+) T cells. We find a distinct pattern of IL-2R signaling in which the Janus kinase/STAT pathway remains intact, whereas IL-2 does not activate downstream targets of phosphatidylinositol 3-kinase. Negative regulation of phosphatidylinositol 3-kinase signaling and IL-2-mediated proliferation of CD4(+)CD25(+) T cells is inversely associated with expression of the phosphatase and tensin homologue deleted on chromosome 10, PTEN.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Division / immunology
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Cell Survival / immunology
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Cells, Cultured
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Down-Regulation / immunology
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Growth Inhibitors / physiology
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / physiology
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Mice
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Mice, Inbred BALB C
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Oligonucleotide Array Sequence Analysis
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Protein Tyrosine Phosphatases / antagonists & inhibitors
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Protein Tyrosine Phosphatases / biosynthesis
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptors, Antigen, T-Cell / immunology
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Receptors, Interleukin-2 / biosynthesis*
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Receptors, Interleukin-2 / physiology*
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Signal Transduction / immunology*
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / enzymology
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism*
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / biosynthesis
Substances
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Growth Inhibitors
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Interleukin-2
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Receptors, Antigen, T-Cell
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Receptors, Interleukin-2
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Transcription Factors
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Tumor Suppressor Proteins
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Protein Tyrosine Phosphatases
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PTEN Phosphohydrolase
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Pten protein, mouse