Dectin-1/2–induced autocrine PGE2 signaling licenses dendritic cells to prime Th2 responses

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.

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

“…[12][13][14][15][16] Several studies have addressed the mode of immunomodulation induced by different helminth-derived products, which appear to possess an ability to down-regulate gene expression of TLR4 signaling-associated molecules such as MYD88, IRAK2, IRF8, JUN, RELA and TLR4, 17 thereby inhibiting synthesis of pro-inflammatory cytokines (IL-12p70, tumor necrosis factor-a (TNF-a)) and chemokines (Chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES), and macrophage inflammatory protein-1b (CCL4)). 14,19,20 Collectively, these modulations result in a DC phenotype that is able to promote Th2 polarization, as confirmed by DC-T-cell co-culturing experiments. 14,19,20 Collectively, these modulations result in a DC phenotype that is able to promote Th2 polarization, as confirmed by DC-T-cell co-culturing experiments.…”

“…40 Predominant down-regulation of the MyD88dependent pathway is supported by the observation that helminth PCF treatment down-regulated TNF, IL6, IL12A, IL12B and PTGS2 transcript levels, which are primarily induced after MyD88-dependent pathway activation. 14,17,18,20 In soluble egg antigen, one of the multiple compounds that can induce DC-mediated Th2 immune responses is omega-1; a glycosylated T2 RNase that can inhibit pro-inflammatory protein synthesis, induce strong surface expression of OX40L on DCs and increase the IL-4/IFN-c ratio in DCs and allogenic naive CD4 + T-cell co-culturing experiments. 63 Understanding DC-mediated Th2 induction has been a long-standing focus in immunology and is mainly based on studies wherein soluble egg antigen (SEA) from Schistosoma mansoni and T. suis soluble products were employed to initiate DC-mediated Th2 immune response.…”

“…14,17,18,20 In soluble egg antigen, one of the multiple compounds that can induce DC-mediated Th2 immune responses is omega-1; a glycosylated T2 RNase that can inhibit pro-inflammatory protein synthesis, induce strong surface expression of OX40L on DCs and increase the IL-4/IFN-c ratio in DCs and allogenic naive CD4 + T-cell co-culturing experiments. 20 The observations in our study, and the study by Midttun et al 58 that helminth PCF down-regulated PTGS2 transcripts as well as COX-2 protein levels indicate that helminth PCF-treated moDCs might not be able to induce prostaglandin E 2 -dependent DC-mediated Th2 responses. 58 Moreover, a recent study showed that soluble egg antigen treatment of DCs induced prostaglandin E 2 synthesis, resulting in autocrine induced OX40L, which further primed DCs to initiate Th2 responses.…”

“…From this, it appears that helminth PCF-treated moDCs hold a limited potential to polarize and amplify Th1 and Th17 immune responses. Recently, the COX-2 product prostaglandin E 2 has been shown to be involved in DC-mediated Th2 polarization in an autocrine manner 20 and has also been shown to induce expression of the Th2 and Treg chemo-attractant CCL22 in inflammatory DCs. However, expression of IRF4, which is critical for DC-mediated Th2 differentiation, 48 remained unaffected by helminth PCF.…”

RNA‐Sequencing of ovine PBMC after exposure to Haemonchus contortus larval antigen

“…Similarly, TLR4 mediation of MyD88 signalling confers protection during Leishmania donovani infection . C‐type lectin receptors in parasite infections have been shown to activate dendritic cells (DC) in the context of Schistosoma mansoni infection, and parasite binds dectin‐1/2 receptors on DC activating the signal release of eicosanoid prostaglandin E2 (PGE 2 ) which in turn enables DC to promote Th2 differentiation . C‐type lectin receptors can also affect TLR signalling and regulating adaptive immune responses…”