Thrombospondin-1 and indoleamine 2,3-dioxygenase are major targets of extracellular ATP in human dendritic cells.
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-gamma (IFN-gamma) 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.
Marteau
Frédéric
F
Institute of Interdisciplinary Research, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium.
Gonzalez
Nathalie Suarez
NS
Communi
David
D
Goldman
Michel
M
Boeynaems
Jean-Marie
JM
Communi
Didier
D
D000255:Adenosine Triphosphate / Q000378:metabolism*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D045604:Extracellular Fluid / Q000737:chemistry; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000276:immunology; D013058:Mass Spectrometry; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000276:immunology*; D019700:Thrombospondin 1 / Q000096:biosynthesis* / Q000276:immunology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D019700:Thrombospondin 1; D000255:Adenosine Triphosphate