Abstract
Human plasmacytoid dendritic cells (PDCs) can drive naive, allogeneic CD4(+)CD25(-) T cells to differentiate into CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). However, the intracellular mechanism or mechanisms underlying PDC-induced Treg generation are unknown. In this study, we show that human PDCs express high levels of IDO, an intracellular enzyme that catabolizes tryptophan degradation. Triggering of TLR 9 with CpG oligodeoxynucleotides activates PDCs to up-regulate surface expression of B7 ligands and HLA-DR Ag, but also significantly increases the expression of IDO and results in the generation of inducible Tregs from CD4(+)CD25(-) T cells with potent suppressor cell function. Blocking IDO activity with the pharmacologic inhibitor 1-methyl-D-tryptophan significantly abrogates PDC-driven inducible Treg generation and suppressor cell function. Adding kynurenine, the immediate downstream metabolite of tryptophan, bypasses the 1-methyl-D-tryptophan effect and restores PDC-driven Treg generation. Our results demonstrate that the IDO pathway is essential for PDC-driven Treg generation from CD4(+)CD25(-) T cells and implicate the generation of kynurenine pathway metabolites as the critical mediator of this process.
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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Adjuvants, Immunologic / pharmacology
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B7-1 Antigen / biosynthesis
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B7-1 Antigen / immunology
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Cell Differentiation / drug effects
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Cell Differentiation / immunology*
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Cells, Cultured
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Coculture Techniques
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Dendritic Cells / enzymology
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Dendritic Cells / immunology*
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Enzyme Inhibitors / pharmacology
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / immunology*
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HLA-DR Antigens / biosynthesis
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HLA-DR Antigens / immunology
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Humans
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Indoleamine-Pyrrole 2,3,-Dioxygenase / biosynthesis
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Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology*
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Kynurenine / antagonists & inhibitors
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Kynurenine / pharmacology
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Oligodeoxyribonucleotides / pharmacology
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Plasma Cells / enzymology
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Plasma Cells / immunology*
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T-Lymphocytes, Regulatory / enzymology
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T-Lymphocytes, Regulatory / immunology*
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Toll-Like Receptor 9 / immunology
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Toll-Like Receptor 9 / metabolism
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Tryptophan / analogs & derivatives
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Tryptophan / antagonists & inhibitors
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Tryptophan / pharmacology
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Up-Regulation / drug effects
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Up-Regulation / immunology
Substances
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Adjuvants, Immunologic
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B7-1 Antigen
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CPG-oligonucleotide
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Enzyme Inhibitors
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FOXP3 protein, human
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Forkhead Transcription Factors
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HLA-DR Antigens
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Indoleamine-Pyrrole 2,3,-Dioxygenase
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Oligodeoxyribonucleotides
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Toll-Like Receptor 9
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Kynurenine
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Tryptophan