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This conveys antiviral effects, activates other immune cells (NK cells, conventional DCs, B, and T cells), and causes the induction and expansion of a strong inflammatory response. pDCs are key players in various type I IFN\u2013driven autoimmune diseases such as systemic lupus erythematosus or psoriasis, but pDCs are also involved in (anti-)tumor immunity. The sphingolipid sphingosine-1-phosphate (S1P) signals through five G-protein\u2013coupled receptors (S1PR1\u20135) to regulate, among other activities, immune cell migration and activation. The present study shows that S1P stimulation of human, primary pDCs substantially decreases IFN-\u03b1 production after TLR7\/9 activation with different types of CpG oligodeoxynucleotides or tick-borne encephalitis vaccine, which occurred in an S1PR4-dependent manner. Mechanistically, S1PR4 activation preserves the surface expression of the human pDC-specific inhibitory receptor Ig-like transcript 7. We provide novel information that Ig-like transcript 7 is rapidly internalized upon receptor-mediated endocytosis of TLR7\/9 ligands to allow high IFN-\u03b1 production. This is antagonized by S1PR4 signaling, thus decreasing TLR-induced IFN-\u03b1 secretion. At a functional level, attenuated IFN-\u03b1 production failed to alter Ag-driven T cell proliferation in pDC-dependent T cell activation assays, but shifted cytokine production of T cells from a Th1 (IFN-\u03b3) to a regulatory (IL-10) profile. In conclusion, S1PR4 agonists block human pDC activation and may therefore be a promising tool to restrict pathogenic IFN-\u03b1 production.<\/jats:p>","DOI":"10.4049\/jimmunol.1403168","type":"journal-article","created":{"date-parts":[[2016,1,19]],"date-time":"2016-01-19T02:33:27Z","timestamp":1453170807000},"page":"1579-1590","source":"Crossref","is-referenced-by-count":41,"title":["S1PR4 Signaling Attenuates ILT 7 Internalization To Limit IFN-\u03b1 Production by Human Plasmacytoid Dendritic Cells"],"prefix":"10.1093","volume":"196","author":[{"given":"Christina","family":"Dillmann","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt , 60590 Frankfurt ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Ringel","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt , 60590 Frankfurt ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Ringleb","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt , 60590 Frankfurt ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7276-3838","authenticated-orcid":false,"given":"Javier","family":"Mora","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt , 60590 Frankfurt ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Olesch","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt , 60590 Frankfurt ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika F","family":"Fink","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt , 60590 Frankfurt ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Br\u00fcne","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt , 60590 Frankfurt ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Weigert","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt , 60590 Frankfurt ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,2,15]]},"reference":[{"key":"2025030702132223100_r1","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/j.0105-2896.2009.00881.x","article-title":"Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance","volume":"234","author":"Swiecki","year":"2010","journal-title":"Immunol. 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