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

J Immunol. 2016 Feb 15;196(4):1579-90. doi: 10.4049/jimmunol.1403168. Epub 2016 Jan 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • CPG-oligonucleotide
  • Cytokines
  • IL10 protein, human
  • Interferon-alpha
  • LILRA4 protein, human
  • Lysophospholipids
  • Oligodeoxyribonucleotides
  • Receptors, Immunologic
  • Receptors, Lysosphingolipid
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Interleukin-10
  • sphingosine 1-phosphate
  • Sphingosine