Normal development and functions of immune cells require adenosine deaminase (ADA) activity. Absence or low-level ADA in humans results in severe combined immunodeficiency (SCID), which is characterized by hypoplastic thymus, T lymphocyte depletion, and autoimmunity. ADA SCID is currently explained only by intracellular lymphotoxicity of accumulated adenosine. We recently proposed the signaling role of extracellular adenosine (extAdo) in pathogenesis of ADA-SCID and it has been demonstrated that under conditions of ADA deficiency, extAdo antagonizes TCR-triggered signaling and blocks the upregulation both of activation markers and of early activation events in thymocytes. We found that under conditions of ADA deficiency, long-term (4-day) survival of TCR-triggered thymocytes in vitro was accomplished by blocking the adenosine transporter-mediated accumulation of toxic intracellular adenosine. The surviving thymocytes had nonactivated phenotype because of extAdo-mediated, TCR-antagonizing signaling. Thus, the experimental data are consistent with the model where the intracellular toxicity of adenosine is mostly responsible for lymphocyte depletion, whereas extAdo interferes with normal differentiation and functioning of those 20% to 30% of T cells that do survive under conditions of ADA deficiency. Our ongoing studies of ADA- deficient mice considered to represent a model of the ADA SCID disease in humans are complicated by their short life span. Because mice die at about 25 days after birth, the analysis of their immune system functioning is limited to mostly short-term read-outs and analysis of ex vivo lymphocytes. Experiments are in progress to test the prediction that thymocyte and T cell activation in vivo are affected in ADA deficient mice. - Adenosine deaminase, immunodeficiency, T-cells, extracellular adenosine, purinergic receptors