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: Miguel A Tam, Mary Jo Wick
• Journal: Immunology (Immunology) Vol. 128 Issue 3 Pg. 429-38 (Nov 2009) ISSN: 1365-2567 [Electronic] England
• PMID: 20067542 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-1 Antigen
• B7-2 Antigen
• Interferon-alpha
• Myeloid Differentiation Factor 88
• Interferon-beta
• Interferon-gamma

Topics

• Animals
• B7-1 Antigen (biosynthesis, genetics)
• B7-2 Antigen (biosynthesis, genetics)
• CD8-Positive T-Lymphocytes (immunology, metabolism, microbiology, pathology)
• Cell Differentiation
• Dendritic Cells (immunology, metabolism, microbiology, pathology)
• Immunologic Memory
• Interferon-alpha (genetics, metabolism)
• Interferon-beta (genetics, metabolism)
• Interferon-gamma (metabolism)
• Listeriosis (immunology, metabolism, pathology)
• Lymphocyte Activation
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• Signal Transduction