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.
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.
Boullart
A C Inge
AC
Department of Tumor Immunology, Nijmegen Centre for Molecular Life Science, Radboud University Nijmegen Medical Centre, P.O.Box 9101, 6500 HB Nijmegen, The Netherlands.
Aarntzen
Erik H J G
EH
Verdijk
Pauline
P
Jacobs
Joannes F M
JF
Schuurhuis
Danita H
DH
Benitez-Ribas
Daniel
D
Schreibelt
Gerty
G
van de Rakt
Mandy W M M
MW
Scharenborg
Nicole M
NM
de Boer
Annemiek
A
Kramer
Matthijs
M
Figdor
Carl G
CG
Punt
Cornelis J A
CJ
Adema
Gosse J
GJ
de Vries
I Jolanda M
IJ
D023201:CD40 Ligand / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis*; D008024:Ligands; D009000:Monocytes / Q000166:cytology; D011070:Poly I-C / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000502:physiology; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000502:physiology; D051193:Toll-Like Receptors / Q000819:agonists* / Q000502:physiology
D007093:Imidazoles; D008024:Ligands; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma; D015232:Dinoprostone; D011070:Poly I-C; C402365:resiquimod