Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL)

Blood. 2006 May 1;107(9):3617-23. doi: 10.1182/blood-2005-08-3419. Epub 2006 Jan 5.

Abstract

Plasmacytoid dendritic cell precursors (pDCs) are professional type I interferon-producing cells, a critical cell type in regulating innate and adaptive immune responses. By microarray gene expression analysis, we found that pDCs activated by virus or CpG-ODN preferentially express the ligand for the glucocorticoid-induced tumor necrosis factor receptor (GITRL), which was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry analysis. Using the same approaches, we found GITR is expressed by activated natural killer (NK) cells and T cells. We show that pDCs activated by CpG-ODN promote NK cell cytotoxicity and interferon (IFN)-gamma production through type I IFNs and GITRL. Using a GITRL-transfected cell line, we further demonstrate that GITRL promotes NK cell cytotoxicity and IFN-gamma production in synergy with interleukin-2 (IL-2), IFN-alpha, and NKG2D triggering. We also demonstrated that pDCs localized in close contact to NK cells in T-cell areas of the tonsils, and a subpopulation of the pDCs expressed GITRL. This study reveals a novel function of GITR/GITRL in pDC-mediated coactivation of NK cells.

MeSH terms

  • Base Sequence
  • Cell Line
  • Cytotoxicity, Immunologic
  • DNA / genetics
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Gene Expression
  • Glucocorticoid-Induced TNFR-Related Protein
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / immunology*
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • In Vitro Techniques
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Oligodeoxyribonucleotides / pharmacology
  • Oligonucleotide Array Sequence Analysis
  • Palatine Tonsil / cytology
  • Palatine Tonsil / immunology
  • Plasma Cells / drug effects
  • Plasma Cells / immunology*
  • Plasma Cells / metabolism*
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / metabolism
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Recombinant Proteins / pharmacology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Transfection
  • Tumor Necrosis Factors / genetics
  • Tumor Necrosis Factors / metabolism*
  • Tumor Necrosis Factors / pharmacology

Substances

  • CPG-oligonucleotide
  • Glucocorticoid-Induced TNFR-Related Protein
  • Oligodeoxyribonucleotides
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Recombinant Proteins
  • TNFRSF18 protein, human
  • TNFSF18 protein, human
  • Tumor Necrosis Factors
  • Interferon-gamma
  • DNA