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Synergize in the Activation and Maturation of Human Dendritic Cells1
Division of Clinical Pharmacology, Department of Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
Extracellular ATP mediates numerous biological activities by
interacting with plasma membrane P2 purinergic receptors. Recently, P2
receptors have been described on dendritic cells (DC), but their
functional role remains unclear. Proposed functions include improved Ag
presentation, cytokine production, chemotaxis, and induction of
apoptosis. We investigated the effects of ATP and of other P2 receptor
agonists on endocytosis, phenotype, IL-12 secretion, and T cell
stimulatory capacity of human monocyte-derived DC. We found that in the
presence of extracellular ATP, DC transiently increase their
endocytotic activity. Subsequently, DC up-regulate CD86, CD54, and
MHC-II; secrete IL-12; and exhibit an improved stimulatory capacity for
allogeneic T cells. These effects were more pronounced when chemically
modified ATP derivatives with agonistic activity on P2 receptors, which
are resistent to degradation by ectonucleotidases, were applied.
Furthermore, ATP and TNF-
synergized in the activation of DC.
Stimulated with a combination of ATP and TNF-, DC expressed the
maturation marker CD83, secreted large amounts of IL-12, and were
potent stimulators of T cells. In the presence of the P2 receptor
antagonist suramin, the effects of ATP were completely abolished. Our
results suggest that extracellular ATP may play an important
immunomodulatory role by activating DC and by skewing the immune
reaction toward a Th1 response through the induction of IL-12
secretion.
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