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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6102-6111. Prepublished online as a Blood First Edition Paper on April 14, 2009; DOI 10.1182/blood-2008-12-195354. This Article Full Text Full Text (PDF) Supplemental Methods All Versions of this Article: blood-2008-12-195354v1 113/24/6102    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 HighWire Citing Articles via CrossRef Google Scholar Articles by Sharma, M. D. Articles by Munn, D. H. PubMed PubMed Citation Articles by Sharma, M. D. Articles by Munn, D. H. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes Madhav D. Sharma1,2, De-Yan Hou1,2, Yanjun Liu2, Pandelakis A. Koni2,3, Richard Metz4, Phillip Chandler2,3, Andrew L. Mellor2,3, Yukai He2,3, and David H. Munn1,2 1 Department of Pediatrics, 2 Cancer Immunotherapy Program, and 3 Department of Medicine, Medical College of Georgia, Augusta; and 4 Lankenau Institute for Medical Research, Wynnewood, PA The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by a subset of murine plasmacytoid DCs (pDCs) in tumor-draining lymph nodes (TDLNs), where it can potently activate Foxp3+ regulatory T cells (Tregs). We now show that IDO functions as a molecular switch in TDLNs, maintaining Tregs in their normal suppressive phenotype when IDO was active, but allowing inflammation-induced conversion of Tregs to a polyfunctional T-helper phenotype similar to proinflammatory T-helper-17 (TH17) cells when IDO was blocked. In vitro, conversion of Tregs to the TH17-like phenotype was driven by antigen-activated effector T cells and required interleukin-6 (IL-6) produced by activated pDCs. IDO regulated this conversion by dominantly suppressing production of IL-6 in pDCs, in a GCN2-kinase dependent fashion. In vivo, using a model of established B16 melanoma, the combination of an IDO-inhibitor drug plus antitumor vaccine caused up-regulation of IL-6 in pDCs and in situ conversion of a majority of Tregs to the TH17 phenotype, with marked enhancement of CD8+ T-cell activation and antitumor efficacy. Thus, Tregs in TDLNs can be actively reprogrammed in situ into T-helper cells, without the need for physical depletion, and IDO serves as a key regulator of this critical conversion. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. K. Tulic, P. D. Sly, D. Andrews, M. Crook, F. Davoine, S. O. Odemuyiwa, A. Charles, M. L. Hodder, S. L. Prescott, P. G. Holt, et al. Thymic Indoleamine 2,3-Dioxygenase-Positive Eosinophils in Young Children: Potential Role In Maturation of the Naive Immune System Am. J. Pathol., November 1, 2009; 175(5): 2043 - 2052. [Abstract] [Full Text] [PDF] B. Baban, P. R. Chandler, M. D. Sharma, J. Pihkala, P. A. Koni, D. H. Munn, and A. L. Mellor IDO Activates Regulatory T Cells and Blocks Their Conversion into Th17-Like T Cells J. Immunol., August 15, 2009; 183(4): 2475 - 2483. [Abstract] [Full Text] [PDF] D. H. Munn Th17 cells in ovarian cancer Blood, August 6, 2009; 114(6): 1134 - 1135. [Full Text] [PDF] I. Kryczek, M. Banerjee, P. Cheng, L. Vatan, W. Szeliga, S. Wei, E. Huang, E. Finlayson, D. Simeone, T. H. Welling, et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments Blood, August 6, 2009; 114(6): 1141 - 1149. [Abstract] [Full Text] [PDF]

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