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Blood, 16 July 2009, Vol. 114, No. 3, pp. 555-563. Prepublished online as a Blood First Edition Paper on May 22, 2009; DOI 10.1182/blood-2008-11-191197. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-11-191197v1 114/3/555    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chung, D. J. Articles by Young, J. W. Search for Related Content PubMed PubMed Citation Articles by Chung, D. J. Articles by Young, J. W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 24, 2008 Accepted May 13, 2009 Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells David J. Chung*, Marco Rossi, Emanuela Romano, Jennifer Ghith, Jianda Yuan, David H. Munn, and James W. Young Laboratory of Cellular Immunobiology, Memorial Sloan-Kettering Cancer Center, New York, NY, United States Immune Monitoring Facility, Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY, United States Department of Pediatrics, School of Medicine, Medical College of Georgia, Augusta, GA, United States Adult Allogeneic Bone Marrow Transplantation Service, Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, NY, United States * Corresponding author; email: chungd1{at}mskcc.org. 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) upregulate 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+CD25brightFoxp3+CD127neg Tregs. Treg expansion requires moDC contact, CD80/CD86 ligation, and IL-2. Cytofluorographically-sorted CD4+CD25brightFoxp3+ Tregs inhibit as much as 80-90% 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+CD25brightFoxp3+ 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 TGF-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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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