Toward the identification of a tolerogenic signature in IDO-competent dendritic cells.
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-gamma (IFN-gamma), 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.
Orabona
Ciriana
C
Section of Pharmacology, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, 06126 Perugia, Italy.
Puccetti
Paolo
P
Vacca
Carmine
C
Bicciato
Silvio
S
Luchini
Alessandra
A
Fallarino
Francesca
F
Bianchi
Roberta
R
Velardi
Enrico
E
Perruccio
Katia
K
Velardi
Andrea
A
Bronte
Vincenzo
V
Fioretti
Maria Cristina
MC
Grohmann
Ursula
U
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D017931:DNA Primers; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D016209:Interleukin-8 / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D018075:RNA, Complementary / Q000235:genetics; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012882:Skin Tests; D013154:Spleen / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016209:Interleukin-8; D018075:RNA, Complementary; D011994:Recombinant Proteins; C484963:Tyrobp protein, mouse; D007371:Interferon-gamma