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Extracellular Adenine Nucleotides Inhibit the Activation of Human CD4⁺ T Lymphocytes¹

Xavier Duhant^2,*, Liliane Schandené, Catherine Bruyns^*, Nathalie Suarez Gonzalez^*, Michel Goldman, Jean-Marie Boeynaems^*, and Didier Communi^*

^* Institute of Interdisciplinary Research, School of Medicine, Departments of Immunology and Medical Chemistry, Erasme Hospital, Université Libre de Brussels, Brussels, Belgium

ATP has been reported to inhibit or stimulate lymphoid cell proliferation, depending on the origin of the cells. Agents that increase cAMP, such as PGE₂, inhibit human CD4⁺ T cell activation. We demonstrate that several ATP derivatives increase cAMP in both freshly purified and activated human peripheral blood CD4⁺ T cells. The rank order of potency of the various nucleotides was: adenosine 5'-O-(3-thiotriphosphate) (ATPS) 2'- and 3'-O-(4-benzoylbenzoyl) ATP (BzATP) > ATP > 2-methylthio-ATP >> dATP, 2-propylthio-,-dichloromethylene-D-ATP, UDP, UTP. This effect did not involve the activation of A₂Rs by adenosine or the synthesis of prostaglandins. ATPS had no effect on cytosolic calcium, whereas BzATP induced an influx of extracellular calcium. ATPS and BzATP inhibited secretion of IL-2, IL-5, IL-10, and IFN-; expression of CD25; and proliferation after activation of CD4⁺ T cells by immobilized anti-CD3 and soluble anti-CD28 Abs, without increasing cell death. Taken together, our results suggest that extracellular adenine nucleotides inhibit CD4⁺ T cell activation via an increase in cAMP mediated by an unidentified P2YR, which might thus constitute a new therapeutic target in immunosuppressive treatments.

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