Adenosine is an immunosuppressive nucleoside, and adenosine A_2A receptors inhibit T-cell activation. We investigated the role of A_2A receptors in regulating T helper (Th)1- and Th2-cell development and effector function. A_2A-receptor stimulation suppressed the development of T-cell receptor (TCR) -stimulated naive T cells into both Th1 and Th2 cells, as indicated by decreased IFN- production by cells developed under Th1-skewing conditions and decreased interleukin (IL) -4, IL-5, and IL-10 production by cells developed under Th2-skewing conditions. Using A_2A receptor-deficient mice, we demonstrate that A_2A receptor activation inhibits Th1- and Th2-cell development by decreasing the proliferation and IL-2 production of naive T cells, irrespective of whether the cells are expanded under Th1- or Th2-skewing environment. Using in vivo established Th1 and Th2 cells, we further demonstrate the nonselective nature of A_2A receptor-mediated immunosuppressive effects, because A_2A receptor activation decreased IFN- and IL-4 secretion and mRNA level of TCR-stimulated effector Th1 and Th2 cells, respectively. A_2A receptor mRNA expression in both Th1 and Th2 effector cells increased following TCR stimulation. In summary, these data demonstrate that A_2A receptor activation has strong inhibitory actions during early developmental, as well as late effector, stages of Th1- and Th2-cell responses.—Csóka, B., Himer, L., Selmeczy, Z., Vizi, E. S., Pacher, P., Ledent, C., Deitch, E. A., Spolarics, Z., Németh, Z. H., Haskó, G. Adenosine A_2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function.