Thrombospondin-1 and indoleamine 2,3-dioxygenase are major targets of extracellularATP in human dendritic cells

Extracellular adenosine triphosphate af- fects the maturation of human monocyte- derived dendritic cells (DCs), mainly by inhibiting T-helper 1 (Th1) cytokines, pro- moting Th2 cytokines, and modulating the expression of costimulatory mol- ecules. In this study, we report that aden- osine triphosphate (ATP) can induce im- munosuppression through its action on DCs, defining a new role for extracellular nucleotides. Microarray analysis of ATP- stimulated human DCs revealed inter alia a drastic up-regulation of 2 genes encod- ing mediators involved in immunosup- pression: thrombospondin-1 (TSP-1) and indoleamine 2,3-dioxygenase (IDO). The release of TSP-1 by DCs in response to ATP was confirmed at the protein level by enzyme-linked immunosorbent assay (ELISA), immunodetection, and mass spectrometry analysis, and has an anti- proliferative effect on T CD4 lympho- cytes through TSP-1/CD47 interaction. Our pharmacologic data support the in- volvement of purinergic receptor P2Y11 in this ATP-mediated TSP-1 secretion. We demonstrate also that ATP significantly potentiates the up-regulation of IDO—a negative regulator of T lymphocyte prolif- eration—and kynurenine production initi- ated by interferon- (IFN-) in human DCs. Thus, extracellular ATP released from damaged cells and previously consid- ered as a danger signal is also a potent regulator of mediators playing key roles in immune tolerance. Consequently, nu- cleotides' derivatives may be considered as useful tools for DC-based immuno- therapies. (Blood. 2005;106:3860-3866)