Adenosine A2A receptor-mediated cell death of mouse thymocytes involves adenylate cyclase and Bim and is negatively regulated by Nur77

Abstract

Adenosine is generated in the microenvironment of emerging thymocytes through normal mechanisms of lymphocyte selection. In a normal thymus, most of the adenosine is catabolized by adenosine deaminase; however, in an environment where up to 95% of the cells undergo programmed cell death, a sufficient amount of adenosine is accumulated to trigger cell surface adenosine receptors. Here we show that accumulated adenosine can induce apoptosis in immature mouse thymocytes, mostly via adenosine A(2A) receptors. The signaling pathway is coupled to adenylate cyclase activation, induction of the Nur77 transcription factor, Nur77-dependent genes, such as Fas ligand and TRAIL, and the pro-apoptotic BH3-only protein Bim. We analyzed several knockout and transgenic mouse lines and found that adenosine-induced killing of mouse thymocytes requires Bim, occurs independently of "death receptor" signaling and is inhibited by Bcl-2 and Nur77. Collectively our data demonstrate that adenosine-induced cell death involves signaling pathways originally found in negative selection of thymocytes and suggest a determining role of Bim and a regulatory role for Nur77.