Abstract
Naturally arising CD4(+)CD25(+)FoxP3(+) regulatory T cells (nTregs) have an essential role in maintenance of immune homeostasis and peripheral tolerance. Previously, we reported that conventional CD4(+) and CD8(+) T cells undergo p53-induced CD28-dependent apoptosis (PICA) when stimulated with a combination of immobilized anti-CD3 and anti-CD28 Abs, whereas nTregs expand robustly under the same conditions, suggesting that there is a differential survival mechanism against PICA between conventional T cells and nTregs. In this study, we demonstrate that TGF-β signaling is required for nTregs to survive PICA. Conversely, when an active form of exogenous TGF-β is present, conventional T cells become resistant to PICA and undergo robust expansion instead of apoptosis, with reduction of the proapoptotic protein Bim and FoxO3a. A substantial fraction of PICA-resistant T cells expressed IL-9 (T(H)9 cells). Moreover, the presence of IL-6 along with TGF-β led to the generation of T(H)17 cells from conventional T cells. Together, the data demonstrate a novel role for TGF-β in the homeostasis of regulatory T cells and effector T cell differentiation and expansion.
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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Apoptosis / genetics
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Apoptosis / immunology*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / immunology
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Bcl-2-Like Protein 11
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CD8-Positive T-Lymphocytes / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cell Survival / genetics
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Cell Survival / immunology
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Forkhead Box Protein O3
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology
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Interleukin-6 / genetics
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Interleukin-6 / immunology
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Interleukin-9 / genetics
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Interleukin-9 / immunology
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Mice
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Mice, Transgenic
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocytes, Helper-Inducer / immunology*
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / immunology*
Substances
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 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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Interleukin-9
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Membrane Proteins
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Proto-Oncogene Proteins
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Transforming Growth Factor beta