Extracellular nucleitides and their metabolites activate ionotropic P2X and metabotropic P2Y receptors on the surface of various types of cells. Here, we investigated the involvement of P2X and P2Y receptor-mediated signaling in TCR-dependent T cell activation. Murine T cells were activated by stimulation of TCR, and both CD25 expression and interleukin (IL)-2 production were observed in activated T cells. Ecto-nucleotidase apyrase and P2Y(6) antagonist MRS2578 significantly blocked the increases of both CD25 expression and IL-2 production, and P2X(7) antagonists A438079 and oxidized ATP inhibited IL-2 production rather than CD25 expression, suggesting the involvement of P2Y(6) and P2X(7) receptors in different processes of T cell activation. MRS2578 also blocked TCR-dependent elevation of cytosolic Ca2+ in T cells. The P2X(7) and P2Y(6) receptors were expressed in murine CD4 T cells. In conclusion, our results indicate that activation of P2Y(6) and P2X(7) receptors contributes to T cell activation via TCR. (C) 2009 Elsevier Inc. All rights reserved.