IFN‐α enhances CD40 ligand‐mediated activation of immature monocyte‐derived dendritic cells

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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‐1β and/or IL‐4, IFN‐α2a 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‐γ inducing p70 heterodimer, this correlating with higher levels of IFN‐γ secretion by allogeneic T cell subsets and NK cells. Our results suggest that the rapid expression of CD40L, IFN and IL‐1β 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.