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Uncoupling of induced protein processing from maturation in dendritic cells exposed to a highly antigenic preparation from a helminth parasite.

ABSTRACT: 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.

SUBMITTER: Marshall FA

PROVIDER: S-EPMC3893880 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Uncoupling of induced protein processing from maturation in dendritic cells exposed to a highly antigenic preparation from a helminth parasite.

Marshall Fraser A FA Pearce Edward J EJ

Journal of immunology (Baltimore, Md. : 1950) 20081201 11

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, pro ...[more]

PMID: 19017945

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Project description:Schistosomiasis remains an important parasitic disease and a major economic problem in many countries. The Schistosoma mansoni genome and predicted proteome sequences were recently published providing the opportunity to identify new drug candidates. Eukaryotic protein kinases (ePKs) play a central role in mediating signal transduction through complex networks and are considered druggable targets from the medical and chemical viewpoints. Our work aimed at analyzing the S. mansoni predicted proteome in order to identify and classify all ePKs of this parasite through combined computational approaches. Functional annotation was performed mainly to yield insights into the parasite signaling processes relevant to its complex lifestyle and to select some ePKs as potential drug targets.We have identified 252 ePKs, which corresponds to 1.9% of the S. mansoni predicted proteome, through sequence similarity searches using HMMs (Hidden Markov Models). Amino acid sequences corresponding to the conserved catalytic domain of ePKs were aligned by MAFFT and further used in distance-based phylogenetic analysis as implemented in PHYLIP. Our analysis also included the ePK homologs from six other eukaryotes. The results show that S. mansoni has proteins in all ePK groups. Most of them are clearly clustered with known ePKs in other eukaryotes according to the phylogenetic analysis. None of the ePKs are exclusively found in S. mansoni or belong to an expanded family in this parasite. Only 16 S. mansoni ePKs were experimentally studied, 12 proteins are predicted to be catalytically inactive and approximately 2% of the parasite ePKs remain unclassified. Some proteins were mentioned as good target for drug development since they have a predicted essential function for the parasite.Our approach has improved the functional annotation of 40% of S. mansoni ePKs through combined similarity and phylogenetic-based approaches. As we continue this work, we will highlight the biochemical and physiological adaptations of S. mansoni in response to diverse environments during the parasite development, vector interaction, and host infection.

Dataset Information

Uncoupling of induced protein processing from maturation in dendritic cells exposed to a highly antigenic preparation from a helminth parasite.

Publications

Uncoupling of induced protein processing from maturation in dendritic cells exposed to a highly antigenic preparation from a helminth parasite.

Similar Datasets

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