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

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, Ca2
flux, and ERK1/2 signaling and to defective
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 aberrant A2A 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.