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Original Article

Enrico Arpaia^a,b,e, Patricia Benveniste^a,b,e, Antonio Di Cristofano^c, Yiping Gu^a,b,e, Ilan Dalal^a,b,e, Susan Kelly^d, Michael Hershfield^d, Pier Paolo Pandolfi^c, Chaim M. Roifman^a,b,e, and Amos Cohen^a,b,e

^a Division of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
^b Infection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
^c Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, and the Graduate School of Medical Sciences, Cornell University, New York, New York 10021
^d Department of Medicine, Duke University Medical Center, Chapel Hill, North Carolina 27710
^e Department of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
Division of Immunology/Allergy and the Infection, Immunity, Injury, and Repair Program, Research Institute, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada.416-813-8624416-813-8623

croifman{at}sickkids.on.ca

We generated purine nucleoside phosphorylase (PNP)-deficient mice to gain insight into the mechanism of immune deficiency disease associated with PNP deficiency in humans. Similar to the human disease, PNP deficiency in mice causes an immunodeficiency that affects T lymphocytes more severely than B lymphocytes. PNP knockout mice exhibit impaired thymocyte differentiation, reduced mitogenic and allogeneic responses, and decreased numbers of maturing thymocytes and peripheral T cells. T lymphocytes of PNP-deficient mice exhibit increased apoptosis in vivo and higher sensitivity to gamma irradiation in vitro. We propose that the immune deficiency in PNP deficiency is a result of inhibition of mitochondrial DNA repair due to the accumulation of dGTP in the mitochondria. The end result is increased sensitivity of T cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.

Key Words: immune deficiency • apoptosis • mitochondria • purine metabolism • T lymphocyte

Abbreviations used in this paper: ADA, adenosine deaminase; _m, mitochondrial membrane potential; DN, double negative; DP, double positive; MNGIE, neurogastrointestinal encephalomyopathy; PNP, purine nucleoside phosphorylase; SP, single positive; TP, thymidine phosphorylase.

© 2000 The Rockefeller University Press

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