title: S1PR4 Signaling Attenuates ILT 7 Internalization To Limit IFN-α Production by Human Plasmacytoid Dendritic Cells.
abstract: Plasmacytoid dendritic cells (pDCs) produce large amounts of type I IFN in response to TLR7/9 ligands. 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-driven 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-coupled receptors (S1PR1-5) to regulate, among other activities, immune cell migration and activation. The present study shows that S1P stimulation of human, primary pDCs substantially decreases IFN-α 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-α production. This is antagonized by S1PR4 signaling, thus decreasing TLR-induced IFN-α secretion. At a functional level, attenuated IFN-α 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-γ) 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-α production.
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany; and.
authors.forename: Christina
authors.initials: C
authors.lastname: Dillmann
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Ringel
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Ringleb
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany; and.
authors.forename: Javier
authors.identifier: http://orcid.org/0000-0002-7276-3838
authors.initials: J
authors.lastname: Mora
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany; and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Olesch
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany; and.
authors.forename: Annika F
authors.initials: AF
authors.lastname: Fink
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany; and.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany; and weigert@biochem.uni-frankfurt.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
mesh_terms: D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008246:Lysophospholipids / Q000276:immunology / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000276:immunology / Q000502:physiology*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: C408982:CPG-oligonucleotide; D016207:Cytokines; C508609:IL10 protein, human; D016898:Interferon-alpha; C488262:LILRA4 protein, human; D008246:Lysophospholipids; D009838:Oligodeoxyribonucleotides; D011971:Receptors, Immunologic; D049349:Receptors, Lysosphingolipid; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; C060506:sphingosine 1-phosphate; D013110:Sphingosine