MyD88 and interferon‐α/β are differentially required for dendritic cell maturation but dispensable for development of protective memory against Listeria

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Abstract
Summary: Signalling pathways mediated by MyD88 are important for sensing Toll‐like receptor (TLR) ligands and directing an immune response. However, the influence of MyD88‐derived cytokines and interferon (IFN)‐α/β, the latter being made by both MyD88‐dependent and ‐independent pathways, in phenotypic and functional dendritic cell (DC) maturation during infection is poorly understood. Here we investigate the contribution of MyD88‐dependent and ‐independent pathways to DC maturation, CD8 T‐cell activation and the generation of protective memory against Listeria monocytogenes. We show that neither MyD88 deficiency alone nor MyD88/IFN‐αβR double deficiency alters Listeria‐induced costimulatory molecule up‐regulation on DCs in vivo. In contrast, DCs from infected IFN‐αβR−/− mice had higher CD80 and CD86 expression than wild‐type DCs. We then examined the function of DCs matured in infected knockout mice. We found that DCs from Listeria‐infected MyD88−/− and MyD88−/− IFN‐αβR−/− mice induced little or no IFN‐γ by CD8 T cells, respectively. In contrast, DCs from infected IFN‐αβR−/− mice had a greater capacity to induce IFN‐γ compared with DCs from infected wild‐type mice. When the CD8 T‐cell memory response was analysed, infected MyD88−/− and MyD88−/− IFN‐αβR−/− mice were found to have fewer bacteria‐specific memory CD8 T cells than wild‐type mice. However, the fraction of bacteria‐specific CD8 T cells making IFN‐γ was similar in all mouse strains, and MyD88−/− and MyD88−/− IFN‐αβR−/− mice survived lethal challenge. Together the data suggest an inhibitory effect of IFN‐α/β on functional DC maturation during Listeria infection and reveal overlapping roles of MyD88‐induced cytokines and IFN‐α/β in DC maturation and protective anti‐Listeria immunity.

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