Abstract
Regulatory CD4(+) T cells are important for the homeostasis of immune cells, and their absence correlates with autoimmune disorders. However, how the immune system regulates Treg homeostasis remains unclear. We found that IFN-gamma-deficient-mice had more forkhead box P3 (FOXP3(+)) cells than WT mice in all secondary lymphoid organs except the thymus. However, T-bet- or IL-4Ralpha-deficient mice did not show a similar increase. In vitro differentiation studies showed that conversion of naïve T cells into FOXP3(+) cells (neo-generated inducible Treg (iTreg)) by TGF-beta was significantly inhibited by IFN-gamma in a STAT-1-dependent manner. Moreover, an in vivo adoptive transfer study showed that inhibition of FOXP3(+) iTreg generation by IFN-gamma was a T-cell autocrine effect. This inhibitory effect of IFN-gamma on iTreg generation was significantly abrogated after N-acetyl-L-cysteine treatment both in vitro and in vivo, indicating that IFN-gamma regulation of iTreg generation is dependent on ROS-mediated apoptosis. Therefore, our results suggest that autocrine IFN-gamma can negatively regulate the neo-generation of FOXP3(+) iTreg through ROS-mediated apoptosis in the periphery.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / pharmacology
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Animals
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Apoptosis / immunology*
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Cell Differentiation / drug effects
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Female
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Flow Cytometry
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Forkhead Transcription Factors / blood
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Forkhead Transcription Factors / immunology
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Free Radical Scavengers / pharmacology
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Interferon-gamma / deficiency
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Interferon-gamma / genetics
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Interferon-gamma / immunology*
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Interferon-gamma / pharmacology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / immunology*
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Receptors, Cell Surface / blood
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / immunology
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STAT1 Transcription Factor / blood
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STAT1 Transcription Factor / immunology*
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Signal Transduction / immunology
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Specific Pathogen-Free Organisms
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T-Box Domain Proteins / blood
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T-Box Domain Proteins / deficiency
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T-Box Domain Proteins / immunology
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T-Lymphocytes, Regulatory / immunology*
Substances
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Free Radical Scavengers
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Il4ra protein, mouse
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Reactive Oxygen Species
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Receptors, Cell Surface
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STAT1 Transcription Factor
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Stat1 protein, mouse
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Interferon-gamma
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Acetylcysteine