IFN‐α 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.

NADPH oxidase of human dendritic cells: Role in Candida albicans killing and regulation by interferons, dectin‐1 and CD206

“…Here we show that immature DC treatment with IFN-a or IFN-c enhanced the PMA-induced NADPH oxidase activity (Fig.1A, B). A surface phenotype analysis by flow cytometry demonstrated that this effect was not consequent to changes of DC maturation stage, as IFN-c and IFN-a did not induce the expression of the maturation markers CD83, CD86 and CD80 (data not shown), as previously reported [14,16,18].…”

“…For this purpose, we investigated the effect of cytokines able to modulate DC functions such as IFN-a [13][14][15] and IFN-c [16,17] on NADPH oxidase activity and ability of DC to kill Candida albicans. Moreover, we analyzed the DC receptors involved in Candida uptake and their role in NADPH oxidase activation.…”

Type I and II interferons enhance dendritic cell maturation and migration capacity by regulating CD38 and CD74 that have synergistic effects with TLR agonists

“…Treatment of immature DCs with IFN-a results in the upregulation of surface markers, T-cell stimulatory capacities and migration-related chemokines. 16,17 IFN-c also upregulates IL-12 production, CCR7-driven migration, CD38 expression and activated Th1 cell recruitment. 18 Although a combination of IFN and a TLR3 agonist can generate potent DCs, 19,20 optimization of the combination of these stimuli is needed to produce high-quality DCs that can generate potent cytotoxic T lymphocytes and have the ability to migrate to lymph nodes.…”

Distinct Effect of CD40 and TNF-Signaling on the Chemokine/Chemokine Receptor Expression and Function of the Human Monocyte-Derived Dendritic Cells

“…As a member of the TNF-TNFR costimulatory molecule super family, CD40/ CD40L is a key signal for DC maturation into fully functional APCs (14)(15)(16). On the other hand, whether DCs can fully mature depends on their ability to undergo in vivo migration.…”

“…It is generally accepted that CD40/CD40L is a powerful stimulus in DC function and maturation (14)(15)(16). Previous experiments have demonstrated that maturation of DCs through CD40 signaling can promote a protective CD8 T cell mediated immunity that is independent of CD4 T cell help (17).…”