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

Publication ,  Journal Article
Cassani, B; Mirolo, M; Cattaneo, F; Benninghoff, U; Hershfield, M; Carlucci, F; Tabucchi, A; Bordignon, C; Roncarolo, MG; Aiuti, A
Published in: Blood
April 15, 2008

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 www.ClinicalTrials.gov as #NCT00598481 and #NCT0059978.

Duke Scholars

Published In

Blood

DOI

ISSN

0006-4971

Publication Date

April 15, 2008

Volume

111

Issue

8

Start / End Page

4209 / 4219

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Substrate Specificity
  • Signal Transduction
  • Severe Combined Immunodeficiency
  • Receptors, Antigen, T-Cell
  • Receptor, Adenosine A2A
  • Phosphorylation
  • Lymphocyte Activation
  • Intracellular Space
  • Immunology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Cassani, B., Mirolo, M., Cattaneo, F., Benninghoff, U., Hershfield, M., Carlucci, F., … Aiuti, A. (2008). Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. Blood, 111(8), 4209–4219. https://doi.org/10.1182/blood-2007-05-092429
Cassani, Barbara, Massimiliano Mirolo, Federica Cattaneo, Ulrike Benninghoff, Michael Hershfield, Filippo Carlucci, Antonella Tabucchi, Claudio Bordignon, Maria Grazia Roncarolo, and Alessandro Aiuti. “Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients.Blood 111, no. 8 (April 15, 2008): 4209–19. https://doi.org/10.1182/blood-2007-05-092429.
Cassani B, Mirolo M, Cattaneo F, Benninghoff U, Hershfield M, Carlucci F, et al. Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. Blood. 2008 Apr 15;111(8):4209–19.
Cassani, Barbara, et al. “Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients.Blood, vol. 111, no. 8, Apr. 2008, pp. 4209–19. Pubmed, doi:10.1182/blood-2007-05-092429.
Cassani B, Mirolo M, Cattaneo F, Benninghoff U, Hershfield M, Carlucci F, Tabucchi A, Bordignon C, Roncarolo MG, Aiuti A. Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. Blood. 2008 Apr 15;111(8):4209–4219.

Published In

Blood

DOI

ISSN

0006-4971

Publication Date

April 15, 2008

Volume

111

Issue

8

Start / End Page

4209 / 4219

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Substrate Specificity
  • Signal Transduction
  • Severe Combined Immunodeficiency
  • Receptors, Antigen, T-Cell
  • Receptor, Adenosine A2A
  • Phosphorylation
  • Lymphocyte Activation
  • Intracellular Space
  • Immunology