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, Alessandro Aiuti

Research output: Contribution to journalArticlepeer-review


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, Ca 2+ flux, and ERK1/2 signaling and to defective transcriptional events linked to CREB and NF-κB. Moreover, exposure to 2′deoxy-adenosine results in a stronger inhibition of T-cell activation, mediated by the aberrant A 2A adenosine receptor signaling engagement and PKA hyperactiva-tion, 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 www.ClinicalTrials. qov as #NCT00598481 and #NCT0059978.

Original languageEnglish
Pages (from-to)4209-4219
Number of pages11
Issue number8
Publication statusPublished - Apr 15 2008

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


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