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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3859-3867
A2A receptor dependent and A2A receptor
independent effects of extracellular adenosine on murine thymocytes in
conditions of adenosine deaminase deficiency
Sergey Apasov,
Jiang-Fan Chen,
Patrick Smith, and
Michail Sitkovsky
From the Biochemistry and Immunopharmacology Section, Laboratory of
Immunology, NIAID, National Institutes of Health, Bethesda, MD; and
Molecular Neurobiology Laboratory, Department of
Neurology, Massachusetts General Hospital, Harvard Medical School,
Charleston, MA.
Adenosine deaminase (ADA) deficiency causes severe combined
immunodeficiency (SCID) and is accompanied by T-cell depletion and
accumulation of both intracellular and extracellular adenosine (extAdo)
and deoxyadenosine. To better understand the causes of T-cell depletion
in vivo and to discriminate between extracellular and intracellular
effects of exogenously added adenosine in vitro, we investigated
mechanisms of 2 different effects of adenosine on murine thymocytes.
These effects of adenosine include direct induction of apoptosis in
about 6% to 15% thymocytes and inhibition of T-cell receptor
(TCR)-induced activation of the majority of thymocytes with inhibited
ADA. A2A adenosine receptors, but not A2B,
A1, or A3 receptors, are shown to be mostly
responsible for extAdo-triggered signaling (cyclic adenosine
monophosphate [cAMP] accumulation) in murine thymocytes and this
prompted studies of the effects of extAdo on thymocytes from
A2AR gene-deficient mice. It is found that direct apoptotic
effects of extAdo on CD4+CD8+ double
positive (DP) thymocytes are completely accounted for by signaling
through A2AR, with no contribution of intracellular lymphotoxicity or of compensating A2BRs because only
A2AR +/+, but not A2AR  / thymocytes
were susceptible to apoptotic effects of extAdo. Studies of the effects
of cAMP-raising agents support observations of
extAdo/A2AR/cAMP-triggered apoptosis in DP thymocytes. Unexpectedly, the extAdo strongly inhibited TCR-triggered activation of
both A2AR +/+ and A2AR / thymocytes
in the presence of ADA inhibitors. This was confirmed with thymocytes
from ADA gene-deficient mice, suggesting the existence of
A2AR-independent effects of extAdo on thymocytes. The
presented data raises questions about the identity and functional role
of A2AR-expressing thymocytes in T-cell differentiation and
of the role of TCR-antagonizing effects of extAdo in conditions of ADA SCID.
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