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...

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Published in:Blood Vol. 114; no. 3; p. 555
Main Authors: Chung, David J, Rossi, Marco, Romano, Emanuela, Ghith, Jennifer, Yuan, Jianda, Munn, David H, Young, James W
Format: Journal Article
Language:English
Published: United States 16.07.2009
Subjects:
Antigen Presentation
Cell Proliferation
Cells, Cultured
Dendritic Cells - enzymology
Dendritic Cells - immunology
Humans
Immunotherapy
Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics
Indoleamine-Pyrrole 2,3,-Dioxygenase - immunology
Monocytes
T-Lymphocytes - cytology
T-Lymphocytes - immunology
T-Lymphocytes, Cytotoxic
T-Lymphocytes, Regulatory - cytology
T-Lymphocytes, Regulatory - immunology
Up-Regulation - genetics
ISSN:1528-0020, 1528-0020
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Summary: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.
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ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2008-11-191197