Uncoupling of induced protein processing from maturation in dendritic cells exposed to a highly antigenic preparation from a helminth parasite.
TLR ligands induce dendritic cell (DC) maturation. During this process, cells initiate proteolytic degradation of internalized protein Ags into peptides that complex with MHC class II (MHC II) and simultaneously increase expression of costimulatory molecules and of cytokines such as IL-6, IL-12, and IL-23. In these ways, TLR-activated DCs are able to activate naive Th cells and initiate Th1 and Th17 responses, and TLR ligands thus serve as adjuvants for these types of responses. In contrast, products from helminth parasites generally do not activate DCs and act as adjuvants for Th2 response induction. We have explored the underlying basis for this form of adjuvanticity. We show that exposure of DCs to soluble Ags from the eggs of the helminth parasite Schistosoma mansoni (schistosome egg Ag (SEA)) leads to the induction of proteolysis of internalized Ag. This occurs in the absence of significant induction of costimulatory molecule expression or production of proinflammatory cytokines. SEA-induced Ag processing occurs independently of MyD88 or Toll/IL-1 receptor domain containing adaptor inducing IFN-beta (Trif), but is significantly attenuated by inhibition of p38, but not ERK, signaling. In DCs exposed to SEA, ligation of CD40 provides a necessary second signal that stimulates costimulatory molecule expression, allowing DCs to mature into capable APCs. Collectively, the data demonstrate the existence of a MyD88/Trif-independent, p38-dependent pathway of Ag processing in DCs, which is uncoupled from conventional DC maturation and is associated with induction of Th2-type immune responses.
Marshall
Fraser A
FA
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Pearce
Edward J
EJ
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D000947:Antigens, Helminth / Q000276:immunology* / Q000494:pharmacology; D019013:CD40 Antigens / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D015801:Helminth Proteins / Q000276:immunology* / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D012550:Schistosoma mansoni / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D033942:Adaptor Proteins, Vesicular Transport; D000947:Antigens, Helminth; D019013:CD40 Antigens; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D015801:Helminth Proteins; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C055560:p40 egg antigen, Schistosoma