T cell killing in ADA-SCID

Although many different molecular defects can lead to immunodeficiency, mutations in the adenosine deaminase (ADA) gene were the first identified lesions that cause severe combined immunodeficiency (SCID), affecting both B and T cell development. Despite this long history, the cellular events that lead to the death of lymphocytes in children with diseases of purine metabolism, such as ADA-SCID, have never been clear. ADA carries out a crucial step in the catabolism of adenosine and dATP. Because both of these molecules(the former a well known extracellular signaling molecule, and the latter a cytotoxic compound--at least when it is found at levels in excess of the usual cellular reserves for deoxynucleotides) accumulate in the ADA-deficient thymus, Apasov and coworkers have examined T cell development in youn Ada-/- mice. Here they describe events at the stage when CD4/CD8 double negative T cells would normally undergo positive selection. Apasov et al. show that T cell receptor activation in Ada-/- lymphocytes is inhibited by exogenous adenosine, and they suggest a model in which excess extracellular adenosine and toxic levels of dATP cooperate to promote apoptosis of developing T cells. The B cell and NK cell defects seen in these animals were not addressed in this work, but it may be interesting to examine the fate of these cells in ADA deficient animals, considering that a related metabolic disorder, nucleoside phosphorylase deficiency, leads not to SCID but to a specific loss of T cells.