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-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.

Molecular Cloning, Biochemical Characterization, and Partial Protective Immunity of the Heme-Binding GlutathioneS-Transferases from the Human HookwormNecator americanus

“…Further investigations are under way to identify whether the protection of Na-GST-1 immunization is related to neutralization of the enzymatic or heme-binding activities with hamster-specific antibodies and if the lack of protection with Na-GST-2 and Na-GST-3 immunization resulted from the insufficient antibody response. Furthermore, a recent study revealed that a related GST from the liver fluke Fasciola hepatica modulates host immunity by suppressing immune responses associated with chronic inflammation to benefit the parasites' survival within the host (23). Whether hookworm GST is also involved in this protective mechanism is also under investigation.…”

Fasciola hepatica tegumental antigens induce anergic‐like T cells via dendritic cells in a mannose receptor‐dependent manner

“…However, neither PGE2 nor PGD2 were secreted by DCs following stimulation with FhTeg. This immature phenotype that fails to respond to TLR and nonTLR activation [20,42,44] and suppresses T cells in vitro as measured by enhanced GRAIL and CTLA4 by RNA and suppressed cytokine expression in anti-CD3 stimulated CD4 + T cells. Interestingly, the FhTeg-treated DCs do not inhibit CD4 + T-cells proliferation; this points to the DCs partly inducing the anergic phenotype but not fully inducing what is seen during infection.…”

“…However, neither PGE2 nor PGD2 were secreted by DCs following stimulation with FhTeg. This immature phenotype that fails to respond to TLR and nonTLR activation [20,42,44] . We have shown that the action of FhTeg is independent of MR as the lack of anergy induction in DCs generated from knockout mice is not from the inhibition of binding or engagement of the receptor on the DC (manuscript submitted).…”

Fasciola hepatica Fatty Acid Binding Protein Induces the Alternative Activation of Human Macrophages

“…CatL1 and GST have been shown to activate dendritic cells via interaction with the pattern recognition receptor (PRR) Toll-like receptor 4 (TLR4) (15). F. hepatica and other helminth-derived peptides have also shown to suppress the activation of macrophages by microbial stimuli and to alter the response of B cells to cytokine stimulation (17,18).…”

“…Previous studies performed with recombinant forms of F. hepatica proteins, such as CatL1, GST, and TxP, have shown that these proteins interact with cells of immune system in animal model of fascioliasis (14)(15)(16). CatL1 and GST have been shown to activate dendritic cells via interaction with the pattern recognition receptor (PRR) Toll-like receptor 4 (TLR4) (15).…”