Insights into thymic purine metabolism and adenosine deaminase deficiency revealed by transgenic mice overexpressing ecto-5'-nucleotidase (CD73)

• Published in: The Journal of clinical investigation Vol. 99; no. 4; pp. 676 - 683
• Main Authors: Resta, R, Hooker, S W, Laurent, A B, Jamshedur Rahman, S M, Franklin, M, Knudsen, T B, Nadon, N L, Thompson, L F
• Format: Journal Article
• Language: English
• Published: United States 15.02.1997
• Subjects: 5'-Nucleotidase - biosynthesis; Adenosine - metabolism; Adenosine Deaminase - deficiency; Animals; Antibodies, Monoclonal - pharmacology; Apoptosis - immunology; Female; Immunity, Innate; Immunoglobulins - blood; Immunophenotyping; Inosine - metabolism; Lymphocyte Activation; Lymphoid Tissue - cytology; Lymphoid Tissue - enzymology; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Purinergic P1 Receptor Agonists; Purines - metabolism; Radiation Chimera; Reproduction - immunology; Survival Analysis; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - radiation effects; Thymus Gland - enzymology; Thymus Gland - immunology; Thymus Gland - metabolism; Transgenes - immunology
• ISSN: 0021-9738
• DOI: 10.1172/JCI119211

The adenosine producing enzyme ecto-5'-nucleotidase (5'-NT) is not normally expressed during thymocyte development until the medullary stage. To determine whether earlier expression would lead to adenosine accumulation and/or be deleterious for thymocyte maturation, thymic purine metabolism, and T cell differentiation were studied in lckNT transgenic mice overexpressing 5'-NT in cortical thymocytes under the control of the lck proximal promoter. In spite of a 100-fold elevation in thymic 5'-NT activity, transgenic adenosine levels were unchanged and T cell immunity was normal. Inosine, the product of adenosine deamination, was elevated more than twofold, however, indicating that adenosine deaminase (ADA) can prevent the accumulation of adenosine, even with a dramatic increase in 5'-NT activity, and demonstrating the availability of 5'-NT substrates in the thymus for the first time. Thymic adenosine concentrations of mice treated with the ADA inhibitor 2'-deoxycoformycin (dCF) were elevated over 30-fold, suggesting that high ADA activity, rather than an absence of 5'-NT, is mainly responsible for low thymic adenosine levels. The adenosine concentrations in dCF-treated mice are sufficient to cause adenosine receptor-mediated thymocyte apoptosis in vitro, suggesting that adenosine accumulation could play a role in ADA-deficient severe combined immunodeficiency.