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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2846-2854. Prepublished online as a Blood First Edition Paper on December 8, 2005; DOI 10.1182/blood-2005-10-4077. This Article Full Text (PDF) Supplemental Table Erratum (v107,p3441) All Versions of this Article: 2005-10-4077v1 107/7/2846    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Orabona, C. Articles by Grohmann, U. Search for Related Content PubMed PubMed Citation Articles by Orabona, C. Articles by Grohmann, U. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 13, 2005 Accepted November 23, 2005 Towards the identification of a tolerogenic signature in IDO-competent dendritic cells Ciriana Orabona, Paolo Puccetti, Carmine Vacca, Silvio Bicciato, Alessandra Luchini, Francesca Fallarino, Roberta Bianchi, Enrico Velardi, Katia Perruccio, Andrea Velardi, Vincenzo Bronte, Maria C Fioretti, and Ursula Grohmann* Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy Departments of Chemical Engineering Processes and of Oncology and Surgical Sciences, University of Padua, Padua, Italy Department of Experimental Medicine, University of Perugia, Perugia, Italy * Corresponding author; email: ugrohmann{at}tin.it. Although much is known on the transcriptional profiles of dendritic cells (DCs) during maturation, the molecular switches critical for the induction of a tolerogenic program in DC subsets are still obscure. We examined the gene expression profile of murine splenic CD8+ DCs rendered highly tolerogenic by interferon (IFN)-, which activates the enzyme indoleamine 2,3-dioxygenase (IDO, encoded by Indo) and thus initiates the immunosuppressive pathway of tryptophan catabolism. By examining the expression of a series of relevant genes in IDO+ versus IDO- DCs, we found consistent and selective association of the IDO-competent phenotype with down-modulation of the Tyrobp gene, encoding the signaling adapter DAP12, which typically associates with activating receptors. Down-modulation of Tyrobp involved IFN consensus sequence binding protein (ICSBP), a transcription factor also known as IRF-8. In both murine and human monocyte-derived DCs, silencing DAP12 expression imparted IDO functional competence to IDO- cells, whereas silencing IRF-8 in IDO+ counterparts abolished IDO expression and function. Thus, IRF-8 is required in tolerogenic DCs for positive regulation of Indo and negative regulation of Tyrobp. Overall, these studies reveal the occurrence of a simple and evolutionarily conserved code in the control of tolerance by an ancestral metabolic enzyme. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Tolerogenic dendritic cells: a KARAP/DAP12–IRF-8/ICSBP balance Eric Vivier and Marc Dalod Blood 2006 107: 2591-2592. [Full Text] [PDF] This article has been cited by other articles: F. Fallarino, G. Luca, M. Calvitti, F. Mancuso, C. Nastruzzi, M. C. Fioretti, U. Grohmann, E. Becchetti, A. Burgevin, R. Kratzer, et al. Therapy of experimental type 1 diabetes by isolated Sertoli cell xenografts alone J. Exp. Med., October 26, 2009; 206(11): 2511 - 2526. [Abstract] [Full Text] [PDF] D. J. Chung, M. Rossi, E. Romano, J. Ghith, J. Yuan, D. H. Munn, and J. W. Young Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells Blood, July 16, 2009; 114(3): 555 - 563. [Abstract] [Full Text] [PDF] X. Chen, F. Bai, L. Sokol, J. Zhou, A. Ren, J. S. Painter, J. Liu, D. A. Sallman, Y. A. Chen, J. A. Yoder, et al. A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia Blood, April 2, 2009; 113(14): 3226 - 3234. [Abstract] [Full Text] [PDF] A. Curti, S. Trabanelli, V. Salvestrini, M. Baccarani, and R. M. Lemoli The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology Blood, March 12, 2009; 113(11): 2394 - 2401. [Abstract] [Full Text] [PDF] Y.-I. Jeong, S. W. Kim, I. D. Jung, J. S. Lee, J. H. Chang, C.-M. Lee, S. H. Chun, M.-S. Yoon, G. T. Kim, S. W. Ryu, et al. Curcumin Suppresses the Induction of Indoleamine 2,3-Dioxygenase by Blocking the Janus-activated Kinase-Protein Kinase C{delta}-STAT1 Signaling Pathway in Interferon-{gamma}-stimulated Murine Dendritic Cells J. Biol. Chem., February 6, 2009; 284(6): 3700 - 3708. [Abstract] [Full Text] [PDF] C. Orabona, M. T. Pallotta, C. Volpi, F. Fallarino, C. Vacca, R. Bianchi, M. L. Belladonna, M. C. Fioretti, U. Grohmann, and P. Puccetti SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis PNAS, December 30, 2008; 105(52): 20828 - 20833. [Abstract] [Full Text] [PDF] R. Gorczynski, I. Khatri, L. Lee, and I. Boudakov An Interaction between CD200 and Monoclonal Antibody Agonists to CD200R2 in Development of Dendritic Cells That Preferentially Induce Populations of CD4+CD25+ T Regulatory Cells J. Immunol., May 1, 2008; 180(9): 5946 - 5955. [Abstract] [Full Text] [PDF] P. Zhou, J. Teruya-Feldstein, P. Lu, M. 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Frumento, M. Balsamo, C. Cantoni, R. Conte, L. Moretta, A. Moretta, and M. Vitale The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function Blood, December 15, 2006; 108(13): 4118 - 4125. [Abstract] [Full Text] [PDF] L. Gabriele, A. Fragale, P. Borghi, P. Sestili, E. Stellacci, M. Venditti, G. Schiavoni, M. Sanchez, F. Belardelli, and A. Battistini IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features J. Leukoc. Biol., December 1, 2006; 80(6): 1500 - 1511. [Abstract] [Full Text] [PDF] L. Romani, F. Bistoni, K. Perruccio, C. Montagnoli, R. Gaziano, S. Bozza, P. Bonifazi, G. Bistoni, G. Rasi, A. Velardi, et al. Thymosin {alpha}1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance Blood, October 1, 2006; 108(7): 2265 - 2274. [Abstract] [Full Text] [PDF] S. Rutella, S. Danese, and G. Leone Tolerogenic dendritic cells: cytokine modulation comes of age Blood, September 1, 2006; 108(5): 1435 - 1440. [Abstract] [Full Text] [PDF] M. L. Belladonna, U. Grohmann, P. Guidetti, C. Volpi, R. Bianchi, M. C. Fioretti, R. Schwarcz, F. Fallarino, and P. Puccetti Kynurenine Pathway Enzymes in Dendritic Cells Initiate Tolerogenesis in the Absence of Functional IDO J. Immunol., July 1, 2006; 177(1): 130 - 137. [Abstract] [Full Text] [PDF]

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