Maturation of Monocyte-Derived Dendritic Cells With Toll-like Receptor 3 and 7/8 Ligands Combined With Prostaglandin E2 Results in High interleukin-12 Production and Cell Migration

Cancer Immunol Immunother. 2008 Nov;57(11):1589-97. doi: 10.1007/s00262-008-0489-2. Epub 2008 Mar 6.

Abstract

Dendritic cells (DC) are professional antigen-presenting cells of the immune system that play a key role in regulating T cell-based immunity. In vivo, the capacity of DC to activate T cells depends on their ability to migrate to the T cell areas of lymph nodes as well as on their maturation state. Depending on their cytokine-secreting profile, DC are able to skew the immune response in a specific direction. In particular, IL-12p70 producing DC drive T cells towards a T helper 1 type response. A serious disadvantage of current clinical grade ex vivo generated monocyte-derived DC is the poor IL-12p70 production. We have investigated the effects of Toll-like receptor (TLR)-mediated maturation on ex vivo generated human monocyte-derived DC. We demonstrate that in contrast to cytokine-matured DC, DC matured with poly(I:C) (TLR3 ligand) and/or R848 (TLR7/8 ligand) are able to produce vast amounts of IL-12p70, but exhibit a reduced migratory capacity. The addition of prostaglandin E2 (PGE2) improved the migratory capacity of TLR-ligand matured DC while maintaining their IL-12p70 production upon T cell encounter. We propose a novel clinical grade maturation protocol in which TLR ligands poly(I:C) and R848 are combined with PGE2 to generate DC with both high migratory capacity and IL-12p70 production upon T cell encounter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD40 Ligand / metabolism
  • Cell Movement / physiology*
  • Cell Proliferation
  • Cells, Cultured
  • Dendritic Cells / physiology*
  • Dinoprostone / metabolism*
  • Humans
  • Imidazoles / pharmacology
  • Interferon-gamma / metabolism
  • Interleukin-12 / biosynthesis*
  • Ligands
  • Monocytes / cytology
  • Poly I-C / pharmacology
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Toll-Like Receptor 3 / agonists
  • Toll-Like Receptor 3 / physiology
  • Toll-Like Receptor 7 / agonists
  • Toll-Like Receptor 7 / physiology
  • Toll-Like Receptor 8 / agonists
  • Toll-Like Receptor 8 / physiology
  • Toll-Like Receptors / agonists*
  • Toll-Like Receptors / physiology

Substances

  • Imidazoles
  • Ligands
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Toll-Like Receptors
  • CD40 Ligand
  • Interleukin-12
  • Interferon-gamma
  • Dinoprostone
  • Poly I-C
  • resiquimod