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The Indoleamine 2,3-Dioxygenase Pathway Is Essential for Human Plasmacytoid Dendritic Cell-Induced Adaptive T Regulatory Cell Generation¹

Wei Chen^2,*, Xueqing Liang^*, Amanda J. Peterson^*, David H. Munn and Bruce R. Blazar^*

^* Division of Hematology-Oncology, Blood and Marrow Transplantation, Department of Pediatrics and The Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455; and Department of Pediatrics and Immunotherapy Program, Medical College of Georgia, Augusta, GA 30912

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by research Grants from the Randy Shaver Cancer Research Community Fund and the Children’s Cancer Research Fund (to W.C.) and by National Institutes of Health Grants R01AI34495, 2R37HL56067, and P01 AI056299 (to B.R.B.) and R01CA103320, R01CA096651, and R01CA112431 (to D.H.M.).

² Address correspondence and reprint requests to Dr. Wei Chen, University of Minnesota Cancer Center, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, MN 55455. E-mail address: chenw{at}umn.edu

³ Abbreviations used in this paper: PDC, plasmacytoid dendritic cell; DC, dendritic cell; Foxp3, Forkhead box p3 transcriptional repressor; KYN, kynurenine; MFI, mean fluorescence intensity; 1MT, 1-methyl-D-tryptophan; ODN, oligodeoxynucleotide; Treg, regulatory T cell; Trp, tryptophan.

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