IFN-gamma arms human dendritic cells to perform multiple effector functions.
Dendritic cells (DCs) are central players in immunity and are used in immune-adoptive vaccine protocols in humans. IFN-gamma, 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-gamma signaling consequences on MDDC multiple effector functions. IFN-gamma 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-gamma 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-gamma-mediated effects. Thus, IFN-gamma 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.
Frasca
Loredana
L
Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy. lfrasca@iss.it
Nasso
Maria
M
Spensieri
Fabiana
F
Fedele
Giorgio
G
Palazzo
Raffaella
R
Malavasi
Fabio
F
Ausiello
Clara Maria
CM
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D054400:Receptors, CCR7; D018417:Th1 Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism; D015854:Up-Regulation
C515370:CCR7 protein, human; D054400:Receptors, CCR7; D051193:Toll-Like Receptors; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D051997:ADP-ribosyl Cyclase 1