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Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling
Sergey G. Apasov, … , Patrick T. Smith, Michail V. Sitkovsky
Sergey G. Apasov, … , Patrick T. Smith, Michail V. Sitkovsky
Published July 1, 2001
Citation Information: J Clin Invest. 2001;108(1):131-141. https://doi.org/10.1172/JCI10360.
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Article

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

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Abstract

Adenosine deaminase (ADA) 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 ADA-deficient (ADA–/–) mice has enabled the in vivo examination of mechanisms that may underlie the SCID resulting from ADA deficiency. We demonstrate severe depletion of T and B lymphocytes and defects in T and B cell development in ADA–/– mice. T cell apoptosis was abundant in thymi of ADA–/– 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 ADA–/– mice revealed that ADA deficiency is accompanied by TCR activation defects of T cells in vivo. Furthermore, ex vivo experiments 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 vivo confirmed that ADA deficiency reduces tyrosine phosphorylation of TCR-associated signaling molecules and blocks TCR-triggered calcium increases.

Authors

Sergey G. Apasov, Michael R. Blackburn, Rodney E. Kellems, Patrick T. Smith, Michail V. Sitkovsky

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Figure 1

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Demonstration of extensive cell death in thymus but not in peripheral ly...
Demonstration of extensive cell death in thymus but not in peripheral lymphoid organs of ADA–/– mice. (a) Genetic and biochemical evidence of ADA deficiency in screening for ADA+/+, ADA+/–, and ADA–/– mice. Littermates of ADA heterozygous mice were first analyzed by zymogram assay to identify ADA–/– mice, and then tail DNA samples were analyzed by Southern blot as described in ref. 11. Arrowheads on the zymogram indicate position of ADA and hemoglobin (internal control). (b) Comparison of spleens and thymi from ADA+/+ and ADA–/– littermates. ×3. (c) Decreased cellularity of lymphoid organs of ADA–/– mice. n, number of animals analyzed.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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