title: Major secretory antigens of the helminth Fasciola hepatica activate a suppressive dendritic cell phenotype that attenuates Th17 cells but fails to activate Th2 immune responses.
abstract: Fasciola hepatica is a helminth pathogen that drives Th2/Treg immune responses in its mammalian host. The parasite releases a large number of molecules that are critical to inducing this type of immune response. Here we have selected recombinant forms of two major F. hepatica secreted molecules, the protease cathepsin L (rFhCL1) and an antioxidant, sigma class glutathione transferase (rFhGST-si), to examine their interactions with dendritic cells (DCs). Despite enzymatic and functional differences between these molecules, both induced interleukin-6 (IL-6), IL-12p40, and macrophage inflammatory protein 2 (MIP-2) secretion from DCs and enhanced CD40 expression. While this induction was mediated by Toll-like receptor 4 (TLR4), the subsequent intracellular signaling pathways differed; rFhCL1 signaled through p38, and rFhGST-si mediated its effect via c-Jun N-terminal kinase (JNK), p38, p-NF-kappaBp65, and IRF5. Neither rFhCL1 nor rFhGST-si enhanced DC phagocytosis or induced Th2 immune responses in vivo. However, DCs matured in the presence of either enzyme attenuated IL-17 production from OVA peptide-specific T cells in vivo. In addition, DCs exposed to either antigen secreted reduced levels of IL-23. Therefore, both F. hepatica FhCL1 and FhGST-si modulate host immunity by suppressing responses associated with chronic inflammation-an immune modulatory mechanism that may benefit the parasite's survival within the host.
authors.affiliation: Parasite Immune Modulation Group, School of Nursing, Faculty of Science and Health, Dublin City University, Glasnevin, Dublin 9, Ireland.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dowling
authors.forename: Clare M
authors.initials: CM
authors.lastname: Hamilton
authors.forename: Sheila
authors.initials: S
authors.lastname: Donnelly
authors.forename: James
authors.initials: J
authors.lastname: La Course
authors.forename: Peter M
authors.initials: PM
authors.lastname: Brophy
authors.forename: John
authors.initials: J
authors.lastname: Dalton
authors.forename: Sandra M
authors.initials: SM
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D015153:Blotting, Western; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology; D005210:Fasciola hepatica / Q000276:immunology*; D005211:Fascioliasis / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000469:parasitology; D018417:Th1 Cells / Q000276:immunology / Q000469:parasitology; D018418:Th2 Cells / Q000276:immunology / Q000469:parasitology
chemical_list: D000947:Antigens, Helminth; D020381:Interleukin-17