Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients.

Journal Article (Clinical Trial;Journal Article)

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-kappaB. 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 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 as #NCT00598481 and #NCT0059978.

Full Text

Duke Authors

Cited Authors

  • Cassani, B; Mirolo, M; Cattaneo, F; Benninghoff, U; Hershfield, M; Carlucci, F; Tabucchi, A; Bordignon, C; Roncarolo, MG; Aiuti, A

Published Date

  • April 15, 2008

Published In

Volume / Issue

  • 111 / 8

Start / End Page

  • 4209 - 4219

PubMed ID

  • 18218852

Pubmed Central ID

  • PMC2288726

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood-2007-05-092429


  • eng

Conference Location

  • United States