title: IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features.
abstract: Members of the IFN regulatory factors (IRFs) family are transcriptional regulators that play essential roles in the homeostasis and function of the immune system. Recent studies indicate a direct involvement of some members of the family in the development of different subsets of dendritic cells (DC). Here, we report that IRF-1 is a potent modulator of the development and functional maturation of DC. IRF-1-deficient mice (IRF-1(-/-)) exhibited a predominance of plasmacytoid DC and a selective reduction of conventional DC, especially the CD8alpha(+) subset. IRF-1(-/-) splenic DC were markedly impaired in their ability to produce proinflammatory cytokines such as IL-12. By contrast, they expressed high levels of IL-10, TGF-beta, and the tolerogenic enzyme indoleamine 2,3 dioxygenase. As a consequence, IRF-1(-/-) DC were unable to undergo full maturation and retained plasmacytoid and tolerogenic characteristics following virus infection ex vivo and in vivo. Accordingly, DC from IRF-1(-/-) mice were less efficient in stimulating the proliferation of allogeneic T cells and instead, induced an IL-10-mediated, suppressive activity in allogeneic CD4(+)CD25(+) regulatory T cells. Together, these results indicate that IRF-1 is a key regulator of DC differentiation and maturation, exerting a variety of effects on the functional activation and tolerogenic potential of these cells.
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome 00161, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Gabriele
authors.forename: A
authors.initials: A
authors.lastname: Fragale
authors.forename: P
authors.initials: P
authors.lastname: Borghi
authors.forename: P
authors.initials: P
authors.lastname: Sestili
authors.forename: E
authors.initials: E
authors.lastname: Stellacci
authors.forename: M
authors.initials: M
authors.lastname: Venditti
authors.forename: G
authors.initials: G
authors.lastname: Schiavoni
authors.forename: M
authors.initials: M
authors.lastname: Sanchez
authors.forename: F
authors.initials: F
authors.lastname: Belardelli
authors.forename: A
authors.initials: A
authors.lastname: Battistini
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000235:genetics / Q000276:immunology; D045463:Avulavirus Infections / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D050856:Interferon Regulatory Factor-1 / Q000172:deficiency* / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009522:Newcastle disease virus / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D016207:Cytokines; D050856:Interferon Regulatory Factor-1