Abstract
The molecular mechanisms through which dendritic cells (DCs) prime T helper 2 (Th2) responses, including those elicited by parasitic helminths, remain incompletely understood. Here, we report that soluble egg antigen (SEA) from Schistosoma mansoni, which is well known to drive potent Th2 responses, triggers DCs to produce prostaglandin E2 (PGE2), which subsequently—in an autocrine manner—induces OX40 ligand (OX40L) expression to license these DCs to drive Th2 responses. Mechanistically, SEA was found to promote PGE2 synthesis through Dectin-1 and Dectin-2, and via a downstream signaling cascade involving spleen tyrosine kinase (Syk), extracellular signal-regulated kinase (ERK), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (ω-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that ω-1–independent Th2 priming by SEA was mediated by Dectin-2 and Syk signaling in DCs. Finally, we found that Dectin-2−/−, and to a lesser extent Dectin-1−/− mice, displayed impaired Th2 responses and reduced egg-driven granuloma formation following S. mansoni infection, highlighting the physiological importance of this pathway in Th2 polarization during a helminth infection. In summary, we identified a novel pathway in DCs involving Dectin-1/2-Syk-PGE2-OX40L through which Th2 immune responses are induced.
Highlights
Dendritic cells (DCs) are key players in the immune system because of their unique capacity to prime antigen-specific T helper 1 (Th1), T helper 2 (Th2), Th17, or regulatory T cell (Treg) responses tailored against the pathogen they encounter [1,2,3]
T helper 2 (Th2) responses, which are initiated by dendritic cells (DCs), can cause allergic diseases, but they can provide protection against metabolic disorders and parasitic helminth infections
We find that egg antigens from the parasitic helminth Schistosoma mansoni bind to pattern-recognition receptors (PRRs) Dectin-1 and Dectin-2 on DCs
Summary
Dendritic cells (DCs) are key players in the immune system because of their unique capacity to prime antigen-specific T helper 1 (Th1), Th2, Th17, or regulatory T cell (Treg) responses tailored against the pathogen they encounter [1,2,3]. The molecular mechanisms through which DCs prime Th2 responses are still not fully defined. SEA is well recognized for its ability to condition DCs for priming of Th2 responses [9,10,11,12,13]. While ω-1 by itself was sufficient to condition DCs for Th2 polarization, SEA from which ω-1 was depleted still retained most of its Th2 priming potential both in vitro and in vivo. Eggs in which ω-1 expression was silenced [19] retained most of their Th2-polarizing potential, suggesting that there are additional mechanisms through which DCs become conditioned by schistosome eggs to prime Th2 responses [20]
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