MyD88 and IFN-alphabeta differentially control maturation of bystander but not Salmonella-associated dendritic cells or CD11cintCD11b+ cells during infection.
The interface between dendritic cells (DCs) and T cells is critical to elicit effective immunity against pathogens. The maturation state of DCs determines the quality of the interaction and governs the type of response. DCs can be matured directly through activating Toll-like receptors (TLRs) or indirectly by cytokines. We explore the role of the TLR adaptor MyD88 on DC maturation during Salmonella infection. Using Salmonella expressing GFP, we also examine the phenotype and function of bacteria-associated DCs matured in the absence of bacteria-mediated TLR signalling. MyD88 was required for upregulation of CD80 on DCs during infection, whereas CD86 and CD40 were upregulated independently of MyD88, although requiring a higher bacterial burden in the MLN. MyD88-independent upregulation was mediated by IFN-alphabeta produced during infection. In infected MyD88(-/-)IFN-alphabetaR(-/-) mice, which lack most bacteria-driven TLR signalling, indirect DC maturation was abolished. In contrast, DCs containing Salmonella upregulated co-stimulatory molecules independently of MyD88 and IFN-alphabeta, revealing a pathway of phenotypic maturation active in infected DCs. However, despite high co-stimulatory molecule expression, Salmonella-containing DCs from MyD88(-/-) or MyD88(-/-)IFN-alphabetaR(-/-) mice had a compromised capacity to activate T cells. Thus, bacterial stimulation of TLRs influences DC function at multiple levels that modulates their capacity to direct antibacterial immunity.
Tam
Miguel A
MA
Department of Microbiology and Immunology, Göteborg University, 405 30 Göteborg, Sweden.
Sundquist
Malin
M
Wick
Mary Jo
MJ
D000818:Animals; D039481:CD11b Antigen / Q000276:immunology*; D039521:CD11c Antigen / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology; D007372:Interferons / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D012475:Salmonella / Q000276:immunology*; D012480:Salmonella Infections / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D039481:CD11b Antigen; D039521:CD11c Antigen; D016898:Interferon-alpha; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053633:Receptor, Interferon alpha-beta; D007372:Interferons