A 2A adenosine receptors (A 2A AR) inhibit inflammation, although the mechanisms through which adenosine exerts its effects remain unclear. Although the transfer of regulatory Th cells blocks colitis induced by pathogenic CD45RB high Th cells, we show that CD45RB low or CD25+ Th cells from A 2A AR-deficient mice do not prevent disease. Moreover, CD45RB high Th cells from A 2A AR-deficient mice were not suppressed by control CD45RB low Th cells. A 2A AR agonists suppressed the production of proinflammatory cytokines by CD45RB high and CD45RB low T cells in association with a loss of mRNA stability. In contrast, anti-inflammatory cytokines, including IL-10 and TGF-β, were minimally affected. Oral administration of the A 2A AR agonist ATL313 attenuated disease in mice receiving CD45RB high Th cells. These data suggest that A 2A AR play a novel role in the control of T cell-mediated colitis by suppressing the expression of proinflammatory cytokines while sparing anti-inflammatory activity mediated by IL-10 and TGF-β.