Abstract
The cytokine IL-2 plays a very important role in the proliferation and survival of activated T cells. These effects of IL-2 are dependent on signaling through the phosphatidylinositol 3-kinase (PI3K) pathway. We and others have shown that PI3K, through activation of protein kinase B/Akt, inhibits transcriptional activation by a number of forkhead transcription factors (FoxO1, FoxO3, and FoxO4). In this study we have investigated the role of these forkhead transcription factors in the IL-2-induced T cell proliferation and survival. We show that IL-2 regulates phosphorylation of FoxO3 in a PI3K-dependent fashion. Phosphorylation and inactivation of FoxO3 appears to play an important role in IL-2-mediated T cell survival, because mere activation of FoxO3 is sufficient to trigger apoptosis in T cells. Indeed, active FoxO3 can induce expression of IL-2-regulated genes, such as the cdk inhibitor p27(Kip1) and the proapoptotic Bcl-2 family member Bim. Furthermore, we show that IL-2 triggers a rapid, PI3K-dependent, phosphorylation of FoxO1a in primary T cells. Thus, we propose that inactivation of FoxO transcription factors by IL-2 plays a critical role in T cell proliferation and survival.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Apoptosis / immunology
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism*
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / metabolism*
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Cell Line
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Cell Survival / genetics
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Cell Survival / immunology
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p27
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Gene Silencing / immunology
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Humans
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Interleukin-2 / physiology*
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Lymphocyte Activation / genetics
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Membrane Proteins*
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Mice
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Phosphatidylinositol 3-Kinases / physiology
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transcription, Genetic / immunology*
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism*
Substances
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Carrier Proteins
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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DNA-Binding Proteins
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FOXO1 protein, human
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FOXO4 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Interleukin-2
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Membrane Proteins
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Proto-Oncogene Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt