TY - JOUR
T1 - The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation
AU - Chen, Wei
AU - Liang, Xueqing
AU - Peterson, Amanda J.
AU - Munn, David H.
AU - Blazar, Bruce R.
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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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U2 - 10.4049/jimmunol.181.8.5396
DO - 10.4049/jimmunol.181.8.5396
M3 - Article
C2 - 18832696
AN - SCOPUS:54049151564
SN - 0022-1767
VL - 181
SP - 5396
EP - 5404
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -