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

• Published in: Infection and Immunity 2010-02, Vol.78 (2), p.793-801
• Main Authors: Dowling, David J, Hamilton, Clare M, Donnelly, Sheila, La Course, James, Brophy, Peter M, Dalton, John, O'Neill, Sandra M
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Helminth - immunology; Biological and medical sciences; Blotting, Western; Cellular Microbiology: Pathogen-Host Cell Molecular Interactions; Dendritic Cells - immunology; Dendritic Cells - parasitology; Fasciola hepatica; Fasciola hepatica - immunology; Fascioliasis - immunology; Fundamental and applied biological sciences. Psychology; Interleukin-17 - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microbiology; Phenotype; Signal Transduction - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - parasitology; Th1 Cells - immunology; Th1 Cells - parasitology; Th2 Cells - immunology; Th2 Cells - parasitology
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00573-09

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-κBp65, 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.