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IFN- Arms Human Dendritic Cells to Perform Multiple Effector Functions¹

Loredana Frasca^2,*, Maria Nasso^*, Fabiana Spensieri^*, Giorgio Fedele^*, Raffaella Palazzo^*, Fabio Malavasi and Clara Maria Ausiello^*

^* Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome; and Department of Genetics, Biology, and Biochemistry and Research Center for Experimental Medicine, University of Torino Medical School, Turin, Italy

Dendritic cells (DCs) are central players in immunity and are used in immune-adoptive vaccine protocols in humans. IFN-, mandatory in Th-1 polarization and endowed with regulatory properties, is currently used to condition monocyte-derived DCs (MDDC) in cancer therapy and in clinical trials to treat chronic infectious diseases. We therefore performed a wide analysis of IFN- signaling consequences on MDDC multiple effector functions. IFN- itself induced IL-27p28 expression and survival but did not promote relevant CCR7-driven migration or activated Th-1 cell recruitment capacity in MDDC. Administered in association with classical maturation stimuli such as CD40 or TLR-4 stimulation, IFN- up-regulated IL-27 and IL-12 production, CCR7-driven migration, and activated Th-1 cell recruitment, whereas it decreased IL-10 production and STAT3 phosphorylation. CD38 signaling, which orchestrates migration, survival, and Th-1 polarizing ability of mature MDDC, was involved in IFN--mediated effects. Thus, IFN- is a modulator of multiple DC effector functions that can be helpful in MDDC-based vaccination protocols. These data also help understand the dual role exerted by this cytokine as both an inducer and a regulator of inflammation and immune response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Istituto Superiore di Sanità-National Institutes of Health scientific cooperation agreement, Istituto Superiore di Sanità, 6° AIDS project, and Italian Ministry of Health (to C.M.A.).

² Address correspondence and reprint requests to Dr. Loredana Frasca, Department of Infectious, Parasitic, and Immune-Mediated Diseases, Anti-Infectious Immunity Unit, Istituto Superiore di Sanità, 00161 Rome, Italy. E-mail address: lfrasca{at}iss.it

³ Abbreviations used in this paper: DC, dendritic cell; MDDC, monocyte-derived DC; i, immature; m, mature; CD40lig, CD40 ligation; PI, propidium iodide; p, phosphor; nt, untreated; LN, lymph node; SAPK, stress-activated protein kinase; MFI, mean fluorescence intensity.

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