Extracellular adenine nucleotides inhibit the activation of human CD4+ T lymphocytes.
ATP has been reported to inhibit or stimulate lymphoid cell proliferation, depending on the origin of the cells. Agents that increase cAMP, such as PGE(2), 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) (ATPgammaS) approximately 2'- and 3'-O-(4-benzoylbenzoyl) ATP (BzATP) > ATP > 2-methylthio-ATP >> dATP, 2-propylthio-beta,gamma-dichloromethylene-D-ATP, UDP, UTP. This effect did not involve the activation of A(2)Rs by adenosine or the synthesis of prostaglandins. ATPgammaS had no effect on cytosolic calcium, whereas BzATP induced an influx of extracellular calcium. ATPgammaS and BzATP inhibited secretion of IL-2, IL-5, IL-10, and IFN-gamma; 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.
Duhant
Xavier
X
Institute of Interdisciplinary Research, School of Medicine, Department of Immunology, Erasme Hospital, Université Libre de Brussels, Brussels, Belgium. xdulant@ulb.ac.be
Schandené
Liliane
L
Bruyns
Catherine
C
Gonzalez
Nathalie Suarez
NS
Goldman
Michel
M
Boeynaems
Jean-Marie
JM
Communi
Didier
D
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005110:Extracellular Space / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D058910:Purinergic P2 Receptor Agonists; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018048:Receptors, Purinergic P2 / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D007166:Immunosuppressive Agents; C109734:P2RY11 protein, human; D058910:Purinergic P2 Receptor Agonists; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D018048:Receptors, Purinergic P2; C022571:adenosine 5'-O-(3-thiotriphosphate); C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D002118:Calcium