Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells.
A comprehensive understanding of the complex, autologous cellular interactions and regulatory mechanisms that occur during normal dendritic cell (DC)-stimulated immune responses is critical to optimizing DC-based immunotherapy. We have found that mature, immunogenic human monocyte-derived DCs (moDCs) up-regulate the immune-inhibitory enzyme, indoleamine 2,3-dioxygenase (IDO). Under stringent autologous culture conditions without exogenous cytokines, mature moDCs expand regulatory T cells (Tregs) by an IDO-dependent mechanism. The priming of resting T cells with autologous, IDO-expressing, mature moDCs results in up to 10-fold expansion of CD4(+)CD25(bright)Foxp3(+)CD127(neg) Tregs. Treg expansion requires moDC contact, CD80/CD86 ligation, and endogenous interleukin-2. Cytofluorographically sorted CD4(+) CD25(bright)Foxp3(+) Tregs inhibit as much as 80% to 90% of DC-stimulated autologous and allogeneic T-cell proliferation, in a dose-dependent manner at Treg:T-cell ratios of 1:1, 1:5, and as low as 1:25. CD4(+)CD25(bright)Foxp3(+) Tregs also suppress the generation of cytotoxic T lymphocytes specific for the Wilms tumor antigen 1, resulting in more than an 80% decrease in specific target cell lysis. Suppression by Tregs is both contact-dependent and transforming growth factor-beta-mediated. Although mature moDCs can generate Tregs by this IDO-dependent mechanism to limit otherwise unrestrained immune responses, inhibition of this counter-regulatory pathway should also prove useful in sustaining responses stimulated by DC-based immunotherapy.
Chung
David J
DJ
Laboratory of Cellular Immunobiology, Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA. chungd1@mskcc.org
Rossi
Marco
M
Romano
Emanuela
E
Ghith
Jennifer
J
Yuan
Jianda
J
Munn
David H
DH
Young
James W
JW
D017951:Antigen Presentation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology*; D009000:Monocytes; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase