The extracellular versus intracellular mechanisms of inhibition of TCR-triggered activation in thymocytes by adenosine under conditions of inhibited adenosine deaminase

The absence or low levels of adenosine deaminase (:ADA) in humans result in severe combined immunodeficiency (SCID), which is characterized by hypopla stic thymus, T lymphocyte depletion and autoimmunity. Deficiency of ADA cau ses increased levels of both intracellular and extracellular adenosine, alt hough only the intracellular lymphotoxicity of accumulated adenosine is con sidered in the pathogenesis of ADA SCID, It is shown that extracellular but not intracellular adenosine selectively inhibits Ton-triggered up-regulati on of activation markers and apoptotic events in thymocytes under condition s of ADA deficiency. The effects of intracellular adenosine are dissociated from effects of extracellular adenosine in experiments using an adenosine transporter blocker. We found that prevention of toxicity of intracellular adenosine led to survival of TCR-cross-linked thymocytes in long-term (4 da ys) assays, but it was not sufficient for normal T cell differentiation und er conditions of inhibited ADA. Surviving TCR-cross-linked thymocytes had a non-activated phenotype due to extracellular adenosine-mediated, TCR-antag onizing signaling. Taken together the data suggest that both intracellular toxicity and signaling by extracellular adenosine may contribute to pathoge nesis of ADA SCID. Accordingly, extracellular adenosine may act on thymocyt es, which survived intracellular toxicity of adenosine during ADA deficienc y by counteracting TCR signaling. This, in turn, could lead to failure of p ositive and negative selection of thymocytes, and to additional elimination of thymocytes or autoimmunity of surviving T cells.