The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation.
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.
Chen
Wei
W
Division of Hematology-Oncology, Blood and Marrow Transplantation, Department of Pediatrics and The Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA. chenw@umn.edu
Liang
Xueqing
X
Peterson
Amanda J
AJ
Munn
David H
DH
Blazar
Bruce R
BR
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology*; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000276:immunology*; D007737:Kynurenine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010950:Plasma Cells / Q000201:enzymology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D018122:B7-1 Antigen; C408982:CPG-oligonucleotide; D004791:Enzyme Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D007737:Kynurenine; D014364:Tryptophan