Toward the identification of a tolerogenic signature in IDO-competent dendritic cells

Although much is known on the transcriptional profiles of dendritic cells (DCs)during maturation, the molecular switches critical for the induction of a tolerogenicprogram in DC subsets are still obscure. We examined the gene expression profile ofmurine splenic CD8+ DCs rendered highly tolerogenic by interferon (IFN)-γ, whichactivates the enzyme indoleamine 2,3-dioxygenase (IDO, encoded by Indo) and thusinitiates the immunosuppressive pathway of tryptophan catabolism. By examining theexpression of a series of relevant genes in IDO+ versus IDO- DCs, we foundconsistent and selective association of the IDO-competent phenotype with downmodulationof the Tyrobp gene, encoding the signaling adapter DAP12, whichtypically associates with activating receptors. Down-modulation of Tyrobp involvedIFN consensus sequence binding protein (ICSBP), a transcription factor also knownas IRF-8. In both murine and human monocyte-derived DCs, silencing DAP12expression imparted IDO functional competence to IDO- cells, whereas silencing IRF-8 in IDO+ counterparts abolished IDO expression and function. Thus, IRF-8 isrequired in tolerogenic DCs for positive regulation of Indo and negative regulation ofTyrobp. Overall, these studies reveal the occurrence of a simple and evolutionarilyconserved code in the control of tolerance by an ancestral metabolic enzyme.