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Regulation of Oxidative Stress Responses by Ataxia-Telangiectasia Mutated Is Required for T Cell Proliferation¹

Transplantation Research Center, Renal Division, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115

Mutations in the gene encoding ataxia-telangiectasia (A-T) mutated (Atm) cause the disease A-T, characterized by immunodeficiency, the molecular basis of which is not known. Following stimulation through the TCR, Atm-deficient T cells and normal T cells in which Atm is inhibited undergo apoptosis rather than proliferation. Apoptosis is prevented by scavenging reactive oxygen species (ROS) during activation. Atm therefore plays a critical role in T cell proliferation by regulating responses to ROS generated following T cell activation. The inability of Atm-deficient T cells to control responses to ROS is therefore the molecular basis of immunodeficiency associated with A-T.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a grant from the Children’s A-T project and by National Institutes of Health Grant R01AI53666 (to J.I.).

² Address correspondence and reprint requests to Dr. John Iacomini, Transplantation Research Center, Renal Division, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, 221 Longwood Avenue, LM303, Boston, MA 02115. E-mail address: jiacomini{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: A-T, ataxia-telangiectasia; 7-AAD, 7-aminoactinomycin D; Atm, A-T mutated; ATR, A-T related; NAC, N-acetyl cysteine; PI, propidium iodide; ROS, reactive oxygen species.