Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling

Adenosine deaminase (ADA) deficiency in humans results in a severe combined immunodeficiency (SCID). This immunodeficiency is associated with severe d isturbances in purine metabolism chat are thought to mediate lymphotoxicity . The recent generation of ADA-deficient (ADA(-/-)) mice has enabled the in vivo examination of mechanisms that may underlie the SCID resulting from A DA deficiency. We demonstrate severe depletion of T and B lymphocytes and d efects in T and B cell development in ADA(-/-) mice. T cell apoptosis was a bundant in thymi of ADA(-/-) mice, but no increase in apoptosis was detecte d in the spleen and lymph nodes of these animals, suggesting that the defec t is specific to developing thymocytes. Studies of mature T cells recovered from spleens of ADA(-/-) mice revealed that ADA deficiency is accompanied by TCR activation defects of T cells in vivo. Furthermore, ex vivo experime nts on ADA(-/-) T cells demonstrated that elevated adenosine is responsible for this abnormal TCR signaling. These findings suggest that the metabolic disturbances seen in ADA(-/-) mice affect various signaling pathways that regulate thymocyte survival and function. Experiments with thymocytes ex vi vo confirmed that ADA deficiency reduces tyrosine phosphorylation of TCR-as sociated signaling molecules and blocks TCR-triggered calcium increases.