Curtailment of Toll-like receptor signalling and cytokine production in dendritic cells by secreted products of Heligmosomoides polygyrus

Dendritic cells (DCs) are the professional antigen-presenting cells responsible for recognition of pathogens and induction of appropriate adaptive immune responses. Many successful pathogens have evolved to release molecular products that can manipulate DC responses to dampen immunity. Here, we report that the excretory/secretory (ES) products of the intestinal helminth Heligmosomoides polygyrus bakeri profoundly repress the ability of murine and human DCs, differentiated under various conditions, to respond to canonical stimuli delivered through Toll-like Receptors (TLRs). H. polygyrus ES (HES) blocks production of pro-inflammatory cytokines, especially IL-6 and IL-12p70, at both the mRNA and secreted protein levels. In addition, upregulation of the costimulatory molecules CD40, CD80 and CD86 in response to LPS and other TLR ligands is inhibited. Although HES contains a mimic of host TGF-β, inhibition of DC activation is mediated independently of TGF-β signalling and by a HES protein fraction devoid of TGF-β-like proteins; we were not able to recapitulate inhibition with recombinant forms of 5 proteins identified in this fraction. HES pre-treatment of DCs blocks subsequent LPS-induced activation, excluding any direct interference with ligand binding. Inhibition can also be observed if HES is added up to 8 hours after LPS treatment, indicating modulation of later phase intracellular pathways. Analysis of activation of the NF-κB and MAPK signalling pathways and the time courses of CD40, IL-6, IL-12 and TNF expression confirms that HES does not affect the immediate-early phase of TLR-induced activation, but interferes with the ability of DCs to sustain activation and complete the inflammatory response programme, with IL-12 the most susceptible to inhibition as its production is initiated later than that of IL-6 and TNF. These data indicate finely staged changes in the maturation process of DCs upon HES treatment that have not previously been reported, helping explain how parasites like H. polygyrus are able to dramatically modulate host immunity.