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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4209-4219. Prepublished online as a Blood First Edition Paper on January 24, 2008; DOI 10.1182/blood-2007-05-092429.
IMMUNOBIOLOGY Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients1 San Raffaele Telethon Institute for Gene Therapy, Milan, Italy; 2 Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC; 3 Department of Medicina Interna, Scienze Endocrino Metaboliche e Biochimica, University of Siena, Siena, Italy; and 4 Vita-Salute San Raffaele University, Milan, Italy
Mutations in the adenosine deaminase (ADA) gene are responsible for a form of severe combined immunodeficiency (SCID) caused by the lymphotoxic accumulation of ADA substrates, adenosine and 2'-deoxy-adenosine. The molecular mechanisms underlying T-cell dysfunction in humans remain to be elucidated. Here, we show that CD4+ T cells from ADA-SCID patients have severely compromised TCR/CD28-driven proliferation and cytokine production, both at the transcriptional and protein levels. Such an impairment is associated with an intrinsically reduced ZAP-70 phosphorylation, Ca2+ flux, and ERK1/2 signaling and to defective transcriptional events linked to CREB and NF-
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
B. Moreover, exposure to 2'-deoxy-adenosine results in a stronger inhibition of T-cell activation, mediated by the aberrant A2A adenosine receptor signaling engagement and PKA hyperactivation, or in a direct apoptotic effect at higher doses. Conversely, in T cells isolated from patients after gene therapy with retrovirally transduced hematopoietic stem/progenitor cells, the biochemical events after TCR triggering occur properly, leading to restored effector functions and normal sensitivity to apoptosis. Overall, our findings provide a better understanding of the pathogenesis of the immune defects associated with an altered purine metabolism and confirm that ADA gene transfer is an efficacious treatment for ADA-SCID. The trials in this study are enrolled at 
