PGE(2) transiently enhances DC expression of CCR7 but inhibits the ability of DCs to produce CCL19 and attract naive T cells.
Prostaglandin E(2) (PGE(2)) is an inflammatory mediator often used to increase CCR7 expression in the dendritic cells (DCs) used as cancer vaccines and to enhance their responsiveness to lymph node-associated chemokines. Here, we show that high surface expression of CCR7 on PGE(2)-matured DCs is associated with their suppressed production of the endogenous CCR7 ligand, CCL19, and is reversible by exogenous CCL19. In contrast to the PGE(2)-matured DCs, DCs matured in the presence of toll-like receptor (TLR) ligands and interferons produce high levels of both CCL19 and CCR7 mRNA/protein, but show selectively reduced expression of surface CCR7, which is compensated after DC removal from the CCL19-rich maturation environment. In accordance with these findings, PGE(2)-matured DCs show significantly higher in vitro migratory responsiveness to lymph node-associated chemokines directly after DC generation, but not after additional short-term culture in vitro, nor in vivo in patients injected with (111)indium-labeled DCs. The differences in CCL19-producing ability imprinted during DC maturation result in their different abilities to attract CCR7(+) naive T cells. Our data help to explain the impact of PGE(2) on CCR7 expression in maturing DCs and demonstrate a novel mechanism of regulatory activity of PGE(2), mediated by the inhibition of DCs ability to attract naive T cells.
Muthuswamy
Ravikumar
R
Department of Surgery, University of Pittsburgh, PA 15213-1863, USA.
Mueller-Berghaus
Jan
J
Haberkorn
Uwe
U
Reinhart
Todd A
TA
Schadendorf
Dirk
D
Kalinski
Pawel
P
D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D054415:Chemokine CCL19 / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054400:Receptors, CCR7 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*; D051193:Toll-Like Receptors
C515370:CCR7 protein, human; D054415:Chemokine CCL19; D054400:Receptors, CCR7; D051193:Toll-Like Receptors; D015232:Dinoprostone