S1PR4 Signaling Attenuates ILT 7 Internalization To Limit IFN-α Production by Human Plasmacytoid Dendritic Cells

• Published in: The Journal of immunology (1950) 2016-02, Vol.196 (4), p.1579-1590
• Main Authors: Dillmann, Christina, Ringel, Christian, Ringleb, Julia, Mora, Javier, Olesch, Catherine, Fink, Annika F, Roberts, Edward, Brüne, Bernhard, Weigert, Andreas
• Format: Article
• Language: English
• Subjects: Cell Differentiation; Cell Movement; Cells, Cultured; Cytokines - biosynthesis; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Humans; Interferon-alpha - biosynthesis; Interferon-alpha - immunology; Interleukin-10 - biosynthesis; Lymphocyte Activation; Lysophospholipids - immunology; Lysophospholipids - pharmacology; Oligodeoxyribonucleotides - pharmacology; Receptors, Immunologic - immunology; Receptors, Immunologic - physiology; Receptors, Lysosphingolipid - metabolism; Signal Transduction; Sphingosine - analogs & derivatives; Sphingosine - immunology; Sphingosine - pharmacology; Toll-Like Receptor 7 - immunology; Toll-Like Receptor 9 - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1403168

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.