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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3860-3866.
Prepublished online as a Blood First Edition Paper on August 23, 2005; DOI 10.1182/blood-2005-05-1843.
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IMMUNOBIOLOGY
Thrombospondin-1 and indoleamine 2,3-dioxygenase are major targets of extracellular ATP in human dendritic cells
Frédéric Marteau,
Nathalie Suarez Gonzalez,
David Communi,
Michel Goldman,
Jean-Marie Boeynaems, and
Didier Communi
From the Institute of Interdisciplinary Research, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium; Institute for Medical Immunology, IMI, Université Libre de Bruxelles, Gosselies, Belgium; and Department of Medical Chemistry, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Extracellular adenosine triphosphate affects the maturation of human monocyte–derived dendritic cells (DCs), mainly by inhibiting T-helper 1 (Th1) cytokines, promoting Th2 cytokines, and modulating the expression of costimulatory molecules. In this study, we report that adenosine triphosphate (ATP) can induce immunosuppression 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 encoding mediators involved in immunosuppression: 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 antiproliferative effect on T CD4+ lymphocytes through TSP-1/CD47 interaction. Our pharmacologic data support the involvement 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 proliferation—and kynurenine production initiated by interferon- (IFN-) in human DCs.
Thus, extracellular ATP released from damaged cells and previously considered as a danger signal is also a potent regulator of mediators playing key roles in immune tolerance. Consequently, nucleotides' derivatives may be considered as useful tools for DC-based immunotherapies.
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