Journal
JOURNAL OF IMMUNOLOGY
Volume 181, Issue 8, Pages 5396-5404Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.8.5396
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Funding
- Randy Shaver Cancer Research Community Fund
- Children's Cancer Research Fund
- National Institutes of Health [R01AI34495, 2R37HL56067, P01 AI056299, R01CA103320, R01CA096651, R01CA112431]
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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.
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