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oai:repisalud.isciii.es:20.500.12105/66802024-10-31T11:53:11Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Kaiser, Maria M. M. author Ritter, Manuel author del Fresno, Carlos author Jonesdottir, Hulda S. author van der Ham, Alwin J. author Pelgrom, Leonard R. author Schramm, Gabriele author Leyland, Laura E. author Sancho, David author da Costa, Clarissa Prazeres author Giere, Martin author Yazdanbakhsh, Maria author Everts, Bart author 2018 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 (PGE(2)), 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 PGE(2) 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 A(2) (cPLA(2)), and cyclooxygenase 1 and 2 (COX-1 and COX-2). In addition, this pathway was activated independently of the actions of omega-1 (omega-1), a previously described Th2-priming glycoprotein present in SEA. These findings were supported by in vivo murine data showing that w-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-PGE(2)-OX40L through which Th2 immune responses are induced. PLoS Biol. 2018; 16(4):e2005504 1545-7885 http://hdl.handle.net/20.500.12105/6680 29668708 10.1371/journal.pbio.2005504 PLoS Biology Dectin-1/2-induced autocrine PGE(2) signaling licenses dendritic cells to prime Th2 responses