Plasmacytoid dendritic cells (PDCs) are a unique DC subset that plays a critical role in regulating innate and adaptive immune responses. Recently, we have shown that human PDCs activated by CpG oligodeoxynucleotide (CpG ODN) can drive naive, allogeneic CD4+CD25− T cells to differentiate into CD4+CD25+Foxp3+ regulatory T cells (Tregs). However, the intracellular mechanism(s) underlying PDC-induced Treg generation is unknown. Here we show human PDCs express high levels of indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that catabolizes tryptophan degradation. Triggering of Toll-like receptor 9 (TLR9) with CpG oligodeoxynucleotides activates PDCs to upregulate surface expression of B7 ligands and HLA-DR antigen, significantly increases the expression of IDO, and results in the generation of inducible Tregs from CD4+25− T cells with potent suppressor cell function. Blocking IDO activity with a pharmacologic inhibitor 1-methyl-D-tryptophan (1MT) significantly abrogates PDC-driven inducible Treg generation and suppressor cell function. Adding kynurenine (KYN), the immediate downstream metabolite of tryptophan, bypasses the 1MT effect, and restores PDC-driven Treg generation. Our results demonstrate that IDO pathway is essential for PDC-driven Treg generation from CD4+25− T cells, and implicates the generation of KYN-pathway metabolites as the critical mediator of this process.
Disclosure:Research Funding: This work was supported in part by research grants from the Randy Shaver Cancer Research Community Fund and Children’s Cancer Research Fund to W Chen; NIH Grants to B.R. Blazar (R01AI34495, 2R37HL56067, P01 AI056299) and D.H. Munn (R01CA103320, R01CA096651, R01CA112431).