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 journalArticle

48 Citations (Scopus)

Abstract

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
JournalBlood
Volume111
Issue number8
DOIs
Publication statusPublished - Apr 15 2008

Fingerprint

Severe Combined Immunodeficiency
Adenosine Deaminase
T-cells
T-Lymphocytes
Adenosine
Hematopoietic Stem Cells
Adenosine A2A Receptors
Gene transfer
Gene therapy
Phosphorylation
Stem cells
Metabolism
Genetic Therapy
Genes
Chemical activation
Apoptosis
Cytokines
Fluxes
Defects
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. / Cassani, Barbara; Mirolo, Massimiliano; Cattaneo, Federica; Benninghoff, Ulrike; Hershfield, Michael; Carlucci, Filippo; Tabucchi, Antonella; Bordignon, Claudio; Roncarolo, Maria Grazia; Aiuti, Alessandro.

In: Blood, Vol. 111, No. 8, 15.04.2008, p. 4209-4219.

Research output: Contribution to journalArticle

Cassani, B, Mirolo, M, Cattaneo, F, Benninghoff, U, Hershfield, M, Carlucci, F, Tabucchi, A, Bordignon, C, Roncarolo, MG & Aiuti, A 2008, 'Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients', Blood, vol. 111, no. 8, pp. 4209-4219. https://doi.org/10.1182/blood-2007-05-092429
Cassani, Barbara ; Mirolo, Massimiliano ; Cattaneo, Federica ; Benninghoff, Ulrike ; Hershfield, Michael ; Carlucci, Filippo ; Tabucchi, Antonella ; Bordignon, Claudio ; Roncarolo, Maria Grazia ; Aiuti, Alessandro. / Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. In: Blood. 2008 ; Vol. 111, No. 8. pp. 4209-4219.
@article{b8df9b87ef3144569e09c8e3a2219ce1,
title = "Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients",
abstract = "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.",
author = "Barbara Cassani and Massimiliano Mirolo and Federica Cattaneo and Ulrike Benninghoff and Michael Hershfield and Filippo Carlucci and Antonella Tabucchi and Claudio Bordignon and Roncarolo, {Maria Grazia} and Alessandro Aiuti",
year = "2008",
month = "4",
day = "15",
doi = "10.1182/blood-2007-05-092429",
language = "English",
volume = "111",
pages = "4209--4219",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "8",

}

TY - JOUR

T1 - Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients

AU - Cassani, Barbara

AU - Mirolo, Massimiliano

AU - Cattaneo, Federica

AU - Benninghoff, Ulrike

AU - Hershfield, Michael

AU - Carlucci, Filippo

AU - Tabucchi, Antonella

AU - Bordignon, Claudio

AU - Roncarolo, Maria Grazia

AU - Aiuti, Alessandro

PY - 2008/4/15

Y1 - 2008/4/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=43249112042&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43249112042&partnerID=8YFLogxK

U2 - 10.1182/blood-2007-05-092429

DO - 10.1182/blood-2007-05-092429

M3 - Article

C2 - 18218852

AN - SCOPUS:43249112042

VL - 111

SP - 4209

EP - 4219

JO - Blood

JF - Blood

SN - 0006-4971

IS - 8

ER -