IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features

• DOI: 10.1189/jlb.0406246
• Publication Date: 2006-09-12T00:30:33Z
• Authors: L Gabriele; A Fragale; P Borghi; P Sestili; E Stellacci; M Venditti; G Schiavoni; M Sanchez; F Belardelli; A Battistini
• Keywords: Mice, Knockout; 0303 health sciences; Avulavirus Infections; Plasma Cells; Newcastle disease virus; Cell Differentiation; Dendritic Cells; CD8-Positive T-Lymphocytes; T-Lymphocytes, Regulatory; Coculture Techniques; 3. Good health; Mice; 03 medical and health sciences; cytokines; ifn regulatory factors; tolerance; virus infectioas; virus infections; Immune Tolerance; Animals; Arenaviridae Infections; Cytokines; Cells, Cultured; Cell Proliferation; Interferon Regulatory Factor-1

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 CD8α+ 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-β, 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.