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

David J. Dowling, Clare M. Hamilton, Sheila Donnelly, James La Course, Peter M. Brophy, John Dalton, Sandra M. O'Neill

Research output: Contribution to journalArticlepeer-review

114 Citations (Scopus)

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-kappa Bp65, 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
Original languageEnglish
Pages (from-to)793-801
Number of pages9
JournalInfection and Immunity
Volume78
Issue number2
Early online date16 Nov 2009
DOIs
Publication statusPublished - Feb 2010

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