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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.
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IMMUNOBIOLOGY
Toward 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 Cristina Fioretti, and
Ursula Grohmann
From the Departments of Experimental Medicine and Biochemical Sciences and of Clinical and Experimental Medicine, University of Perugia; and the Departments of Chemical Engineering Processes and Oncology and Surgical Sciences, University of Padua, Italy.
Although much is known about 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 profiles 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+ compared with 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 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 the positive regulation of Indo and the 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.
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