title: A(2A) receptor dependent and A(2A) receptor independent effects of extracellular adenosine on murine thymocytes in conditions of adenosine deaminase deficiency.
abstract: 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. A(2A) adenosine receptors, but not A(2B), A(1), or A(3) 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 A(2A)R 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 A(2A)R, with no contribution of intracellular lymphotoxicity or of compensating A(2B)Rs because only A(2A)R +/+, but not A(2A)R -/- thymocytes were susceptible to apoptotic effects of extAdo. Studies of the effects of cAMP-raising agents support observations of extAdo/A(2A)R/cAMP-triggered apoptosis in DP thymocytes. Unexpectedly, the extAdo strongly inhibited TCR-triggered activation of both A(2A)R +/+ and A(2A)R -/- thymocytes in the presence of ADA inhibitors. This was confirmed with thymocytes from ADA gene-deficient mice, suggesting the existence of A(2A)R-independent effects of extAdo on thymocytes. The presented data raises questions about the identity and functional role of A(2A)R-expressing thymocytes in T-cell differentiation and of the role of TCR-antagonizing effects of extAdo in conditions of ADA SCID. (Blood. 2000;95:3859-3867)
authors.affiliation: Biochemistry and Immunopharmacology Section, Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, MD 20982-1892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Apasov
authors.forename: J F
authors.initials: JF
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Sitkovsky
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D005434:Flow Cytometry; D008212:Lymphocyte Depletion; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010627:Phenethylamines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018047:Receptors, Purinergic P1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
chemical_list: D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D011948:Receptors, Antigen, T-Cell; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000242:Cyclic AMP; D000243:Adenosine Deaminase; D000241:Adenosine