Activation of invariant NKT cells by toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids

Immunity. 2007 Oct;27(4):597-609. doi: 10.1016/j.immuni.2007.08.017. Epub 2007 Oct 18.

Abstract

Invariant natural killer T (iNKT) cells are a subset of innate lymphocytes that recognize lipid antigens in the context of CD1d and mediate potent immune regulatory functions via the rapid production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). We investigated whether diverse Toll-like receptor (TLR) signals in myeloid dendritic cells (DCs) could differentially stimulate iNKT cells. Together with the lipopolysaccharide-detecting receptor TLR4, activation of the nucleic acid sensors TLR7 and TLR9 in DCs were particularly potent in stimulating iNKT cells to produce IFN-gamma, but not IL-4. iNKT cell activation in response to TLR9 stimulation required combined synthesis of type I interferon and de novo production of charged beta-linked glycosphingolipid(s) by DCs. In addition, DCs stimulated via TLR9 activated both iNKT cells and NK cells in vivo and protected mice against B16F10-induced melanoma metastases. These data underline the role of TLR9 in iNKT cell activation and might have relevance to infectious diseases and cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidic Glycosphingolipids / immunology*
  • Acidic Glycosphingolipids / metabolism
  • Animals
  • Antigens, CD1 / immunology
  • Antigens, CD1 / metabolism
  • Antigens, CD1d
  • Cells, Cultured
  • Coculture Techniques
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Female
  • Immunotherapy, Adoptive
  • Interferon Type I / immunology*
  • Interferon Type I / metabolism
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Activation / immunology*
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / metabolism
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Toll-Like Receptor 7 / immunology
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 9 / immunology*
  • Toll-Like Receptor 9 / metabolism

Substances

  • Acidic Glycosphingolipids
  • Antigens, CD1
  • Antigens, CD1d
  • Interferon Type I
  • Membrane Glycoproteins
  • RNA, Messenger
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Interferon-gamma