IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features.
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.
Gabriele
L
L
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome 00161, Italy.
Fragale
A
A
Borghi
P
P
Sestili
P
P
Stellacci
E
E
Venditti
M
M
Schiavoni
G
G
Sanchez
M
M
Belardelli
F
F
Battistini
A
A
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
D016207:Cytokines; D050856:Interferon Regulatory Factor-1