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

• Published in: Blood 2005-12, Vol.106 (12), p.3860-3866
• Main Authors: Marteau, Frédéric, Gonzalez, Nathalie Suarez, Communi, David, Goldman, Michel, Boeynaems, Jean-Marie, Communi, Didier
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Biological and medical sciences; Blotting, Western; CD4-Positive T-Lymphocytes - immunology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Enzyme-Linked Immunosorbent Assay; Extracellular Fluid - chemistry; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression; Gene Expression Profiling; Gene Expression Regulation - immunology; Humans; Immunobiology; Indoleamine-Pyrrole 2,3,-Dioxygenase - biosynthesis; Indoleamine-Pyrrole 2,3,-Dioxygenase - immunology; Mass Spectrometry; Modulation of the immune response (stimulation, suppression); Oligonucleotide Array Sequence Analysis; Signal Transduction - immunology; Thrombospondin 1 - biosynthesis; Thrombospondin 1 - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-05-1843

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-γ (IFN-γ) 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.