Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes

Background - We previously used adenosine A(2A) receptor (A2AR) knockout (KO) mice and bone marrow transplantation to show that the infarct-sparing effect of A2AR activation at reperfusion is primarily due to effects on bone marrow-derived cells. In this study we show that CD4(+) but not CD8(+) T lymphocytes contribute to myocardial ischemia/reperfusion injury. Method and Results - After a 45-minute occlusion of the left anterior descending coronary artery and reperfusion, T cells accumulate in the infarct zone within 2 minutes. Addition of 10 mu g/kg of the A2AR agonist ATL146e 5 minutes before reperfusion produces a significant reduction in T-cell accumulation and a significant reduction in infarct size ( percentage of risk area) measured at 24 hours. In Rag1 KO mice lacking mature lymphocytes, infarct size is significantly smaller than in C57BL/6 mice. Infarct size in Rag1 KO mice is increased to the level of B6 mice by adoptive transfer of 50 million CD4(+) T lymphocytes derived from C57BL/6 or A2AR KO but not interferon-gamma KO mice. ATL146e completely blocked the increase in infarct size in Rag1 KO mice reconstituted with B6 but not A2AR KO CD4(+) T cells. The number of neutrophils in the reperfused heart at 24 hours after infarction correlated well with the number of lymphocytes and infarct size. Conclusions - These results strongly suggest that the infarct-sparing effect of A2AR activation is primarily due to inhibition of CD4(+) T-cell accumulation and activation in the reperfused heart.