
<ArticleTitle><prot>Adenosine deaminase</prot> deficiency increases thymic apoptosis and causes defective T cell receptor signaling.</ArticleTitle>
<AbstractText><prot>Adenosine deaminase</prot> (<prot>ADA</prot>) deficiency in humans results in a severe combined immunodeficiency (SCID). This immunodeficiency is associated with severe disturbances in purine metabolism that are thought to mediate lymphotoxicity. The recent generation of <prot>ADA</prot>-deficient (<prot>ADA</prot>(-/-)) mice has enabled the in vivo examination of mechanisms that may underlie the SCID resulting from <prot>ADA</prot> deficiency. We demonstrate severe depletion of T and B lymphocytes and defects in T and B cell development in <prot>ADA</prot>(-/-) mice. T cell apoptosis was abundant in thymi of <prot>ADA</prot>(-/-) mice, but no increase in apoptosis was detected in the spleen and lymph nodes of these animals, suggesting that the defect is specific to developing thymocytes. Studies of mature T cells recovered from spleens of <prot>ADA</prot>(-/-) mice revealed that <prot>ADA</prot> deficiency is accompanied by <prot>TCR</prot> activation defects of T cells in vivo. Furthermore, ex vivo experiments on <prot>ADA</prot>(-/-) T cells demonstrated that elevated adenosine is responsible for this abnormal <?>TCR</?> signaling. These findings suggest that the metabolic disturbances seen in <prot>ADA</prot>(-/-) mice affect various signaling pathways that regulate thymocyte survival and function. Experiments with thymocytes ex vivo confirmed that <prot>ADA</prot> deficiency reduces tyrosine phosphorylation of <prot>TCR</prot>-associated signaling molecules and blocks <prot>TCR</prot>-triggered calcium increases.</AbstractText>
