PDF(Pubmed)
Abstract：
The parasitic helminth Schistosoma mansoni is a potent inducer of type 2 immune responses by stimulating dendritic cells (DCs) to prime T helper 2 (Th2) responses. We previously found that S. mansoni soluble egg antigens (SEA) promote the synthesis of Prostaglandin E2 (PGE2) by DCs through ERK-dependent signaling via Dectin-1 and Dectin-2 that subsequently induces OX40L expression, licensing them for Th2 priming, yet the ligands present in SEA involved in driving this response and whether specific targeting of PGE2 synthesis by DCs could affect Th2 polarization are unknown. We here show that the ability of SEA to bind Dectin-2 and drive ERK phosphorylation, PGE2 synthesis, OX40L expression, and Th2 polarization is impaired upon cleavage of high-mannose glycans by Endoglycosidase H treatment. This identifies high-mannose glycans present on glycoproteins in SEA as important drivers of this signaling axis. Moreover, we find that OX40L expression and Th2 induction are abrogated when microsomal prostaglandin E synthase-1 (mPGES) is selectively inhibited, but not when a general COX-1/2 inhibitor is used. This shows that the de novo synthesis of PGE2 is vital for the Th2 priming function of SEA-stimulated DCs as well as points to the potential existence of other COX-dependent lipid mediators that antagonize PGE2-driven Th2 polarization. Lastly, specific PGE2 inhibition following immunization with S. mansoni eggs dampened the egg-specific Th cell response. In summary, our findings provide new insights in the molecular mechanisms underpinning Th2 induction by S. mansoni and identify druggable targets for potential control of helminth driven-Th2 responses.
摘要：
寄生蠕虫曼氏血吸虫通过刺激树突状细胞（DC）引发T辅助细胞2（Th2）反应，是2型免疫反应的有效诱导剂。我们先前发现曼氏链球菌可溶性卵抗原（SEA）通过Dectin-1和Dectin-2通过ERK依赖性信号促进DCs合成前列腺素E2（PGE2），随后诱导OX40L表达，许可他们进行Th2启动，然而,SEA中存在的配体参与驱动这种反应,以及DC对PGE2合成的特异性靶向是否会影响Th2极化尚不清楚.我们在这里展示了SEA结合Dectin-2并驱动ERK磷酸化的能力，PGE2合成，OX40L表达，和Th2极化在通过内切糖苷酶H处理切割高甘露糖聚糖时受损。这将SEA中糖蛋白上存在的高甘露糖聚糖鉴定为该信号轴的重要驱动因素。此外，我们发现，当微粒体前列腺素E合酶-1（mPGES）被选择性抑制时，OX40L表达和Th2诱导被取消，但不使用一般COX-1/2抑制剂。这表明，PGE2的从头合成对于SEA刺激的DC的Th2启动功能至关重要，并指出可能存在其他COX依赖性脂质介质，它们拮抗PGE2驱动的Th2极化。最后,用S.mansoni卵免疫后的特异性PGE2抑制抑制了卵特异性Th细胞应答。总之,我们的研究结果为支持曼氏链球菌Th2诱导的分子机制提供了新的见解,并确定了潜在控制蠕虫驱动的Th2反应的药物靶标.
