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International Immunology, Vol. 14, No. 4, pp. 367-380, April 2002
© 2002 Japanese Society for Immunology

IFN-{alpha} enhances CD40 ligand-mediated activation of immature monocyte-derived dendritic cells

Thomas Luft2, Petra Luetjens3, Hubertus Hochrein1, Tracey Toy1, Kelly-Anne Masterman1, Mark Rizkalla1, Charlie Maliszewski4, Ken Shortman1, Jonathan Cebon1 and Eugene Maraskovsky1

1 Melbourne Tumour Biology Branch, Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia 2 University of Heidelberg, D69120 Heidelberg, Germany 3 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia 4 Immunex Corp., Seattle, WA 98101, USA

Correspondence to: E. Maraskovsky; E-mail: eugene.maraskovsky{at}ludwig.edu.au
Transmitting editor: A. Kelso

Type I IFN are immune modulatory cytokines that are secreted during early stages of infection. Type I IFN bridge the innate and the adaptive immune system in humans and mice. We compared the capacity of type I and II IFN to induce the functional maturation of monocyte-derived dendritic cells (MoDC). Extending our earlier observation that type I IFN promote DC maturation, we report that these cytokines also enhance DC differentiation by augmenting CD40 ligand (CD40L)-induced cytokine secretion by MoDC. Type I IFN alone were poor inducers of MoDC maturation as compared with other stimuli. They up-regulated the expression of HLA-DR, CD80, CD86, partially CCR7 but not CD83, partially reduced antigen-uptake function, increased the levels of IL-12p35 mRNA, and prolonged surface expression of peptide–MHC class I complexes for presentation to cytotoxic T lymphocytes, but did not induce migration towards CCL21 chemokine. However, type I IFN were potent co-factors for CD40L-mediated function. Here, they enhanced CD40L-mediated IL-6, IL-10 and IL-12p70 secretion. Furthermore, when combined with IL-1ß and/or IL-4, IFN-{alpha}2a type I IFN increased CD40L-mediated IL-12p70 production by 2- to 3-fold, and biased the IL-12 p40/p70 ratio towards the IFN-{gamma} inducing p70 heterodimer, this correlating with higher levels of IFN-{gamma} secretion by allogeneic T cell subsets and NK cells. Our results suggest that the rapid expression of CD40L, IFN and IL-1ß at sites of infection and inflammation can act in concert on immature DC, thereby linking innate and adaptive immune responses. In this way, type I IFN play a dual role as DC maturation factors and enhancers of CD40L-mediated DC activation.

Keywords: cellular activation, cellular differentiation, cytokines, dendritic cells, human


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