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

Abstract

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. © 2009 Blackwell Publishing Ltd.