title: IFN-alpha enhances CD40 ligand-mediated activation of immature monocyte-derived dendritic cells.
abstract: 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-1beta and/or IL-4, IFN-alpha2a 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-1beta 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.
authors.affiliation: Melbourne Tumour Biology Branch, Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Luft
authors.forename: Petra
authors.initials: P
authors.lastname: Luetjens
authors.forename: Hubertus
authors.initials: H
authors.lastname: Hochrein
authors.forename: Tracey
authors.initials: T
authors.lastname: Toy
authors.forename: Kelly-Anne
authors.initials: KA
authors.lastname: Masterman
authors.forename: Mark
authors.initials: M
authors.lastname: Rizkalla
authors.forename: Charlie
authors.initials: C
authors.lastname: Maliszewski
authors.forename: Ken
authors.initials: K
authors.lastname: Shortman
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism; D017951:Antigen Presentation; D000951:Antigens, Neoplasm; D023201:CD40 Ligand / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D003352:Corynebacterium; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology*; D007371:Interferon-gamma / Q000032:analysis*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D053765:Interleukin-12 Subunit p35; D007378:Interleukins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D058965:MART-1 Antigen; D009000:Monocytes / Q000145:classification* / Q000276:immunology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011487:Protein Conformation; D021122:Protein Subunits; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; C508858:IL12A protein, human; D016898:Interferon-alpha; D053765:Interleukin-12 Subunit p35; D007378:Interleukins; D058965:MART-1 Antigen; C548667:MLANA protein, human; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D021122:Protein Subunits; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor