title: MyD88 and interferon-alpha/beta 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)-alpha/beta, 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-alphabetaR double deficiency alters Listeria-induced costimulatory molecule up-regulation on DCs in vivo. In contrast, DCs from infected IFN-alphabetaR(-/-) 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-alphabetaR(-/-) mice induced little or no IFN-gamma by CD8 T cells, respectively. In contrast, DCs from infected IFN-alphabetaR(-/-) mice had a greater capacity to induce IFN-gamma compared with DCs from infected wild-type mice. When the CD8 T-cell memory response was analysed, infected MyD88(-/-) and MyD88(-/- )IFN-alphabetaR(-/-) 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-gamma was similar in all mouse strains, and MyD88(-/-) and MyD88(-/- )IFN-alphabetaR(-/-) mice survived lethal challenge. Together the data suggest an inhibitory effect of IFN-alpha/beta on functional DC maturation during Listeria infection and reveal overlapping roles of MyD88-induced cytokines and IFN-alpha/beta in DC maturation and protective anti-Listeria immunity.
authors.affiliation: Department of Microbiology and Immunology, Göteborg University, Göteborg, Sweden.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Tam
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Wick
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D007156:Immunologic Memory; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D016898:Interferon-alpha; D053594:Myeloid Differentiation Factor 88; D016899:Interferon-beta; D007371:Interferon-gamma