The effect of adenosine mediated suppression of immune cell activation has long been an important topic of study. While the protective benefits of such a signaling mechanism are well recognized, there remains a question as to how dendritic cells (DCs) bypass the high levels of adenosine during tissue stress and infection, and become fully activated. We report here that adenosine receptors on resting stage DCs, both in vivo and in vitro, are functionally desensitized after ligand binding. This desensitization lasts several hours during which DCs are "blind" to adenosine and are stimulated without this negative feedback. This effect is mediated by cAMP signaling. Our report suggests that there is a specific regulatory mechanism used by DCs to overcome adenosine mediated inhibition to become fully activated despite a general suppressive state. (C) 2009 Elsevier Inc. All rights reserved.