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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.
 Previous Article | Next Article 
Submitted May 25, 2007
Accepted November 16, 2007
Altered intracellular and extracellular signaling leads to impaired
T-cell functions in ADA-SCID patients
Barbara Cassani, Massimiliano Mirolo, Federica Cattaneo, Ulrike Benninghoff, Michael Hershfield, Filippo Carlucci, Antonella Tabucchi, Claudio Bordignon, Maria Grazia Roncarolo, and Alessandro Aiuti*
San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy
Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC, United States
Department of Medicine Interna, Scienze Endocrino Metaboliche e Biochimica, University of Siena, Siena, Italy
Vita-Salute San Raffaele University, Milan, Italy
* Corresponding author; email: a.aiuti{at}hsr.it.
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 transcriptional and protein level. Such impairment is associated to an intrinsically reduced ZAP-70 phosphorylation, Ca2+ flux and ERK1/2 signaling, and to a defective activation of the transcriptional events linked to CREB and NF- B. Moreover, exposure to 2'-deoxy-adenosine results in a stronger inhibition of T-cell activation, mediated by the engagement of an aberrant A2A adenosine receptor signaling and PKA hyperactivation, while higher doses of the metabolite lead to a direct apoptotic effect. Conversely, in T cells isolated from patients after autologous transplantation with genetically corrected hematopoietic stem/progenitor cells, the biochemical events following 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 www.ClinicalTrials.gov as #NCT00598481 and #NCT0059978.
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