Key points are not available for this paper at this time.
Accumulation of extracellular and intracellular adenosine (Ado) under hypoxic conditions or in the absence of adenosine deaminase results in lymphocyte depletion and in severe combined immunodeficiency, which are currently explained by direct intracellular lymphotoxicity of Ado metabolites. In support of the alternative, “signaling” mechanism, we show that extracellular Ado (extAdo) suppresses all tested T cell receptor (TCR)-triggered effector functions of T lymphocytes including the TCR-triggered FasL mRNA up-regulation in cytotoxic T lymphocytes. Strong evidence against the intracellular lymphotoxicity of Ado (and in support of the signaling model) is provided by abrogation of TCR-triggered growth inhibition in Ado-exposed T cells. The brief exposure to Ado was sufficient to observe inhibition of TCR-triggered effector functions. The “memory” of T cells to exposure to extAdo is best explained by sustained increases in cAMP. Selective agonist (CGS21680) and antagonist (ZM241385) of A2A adenosine receptor were used in functional assays and cDNA probes for different sybtypes of adenosine receptors were used in Northern blot studies. A2Areceptors are identified as the predominantly expressed subtype of Gs-coupled Ado receptors in T cells. The demonstration of cross-talk between the A2A receptors and TCR in both directions support the possible role of A2A receptors in mechanisms of extAdo-mediated immunosuppression in vivounder adenosine deaminase deficiency and hypoxic conditions in,e.g., solid tumors. Accumulation of extracellular and intracellular adenosine (Ado) under hypoxic conditions or in the absence of adenosine deaminase results in lymphocyte depletion and in severe combined immunodeficiency, which are currently explained by direct intracellular lymphotoxicity of Ado metabolites. In support of the alternative, “signaling” mechanism, we show that extracellular Ado (extAdo) suppresses all tested T cell receptor (TCR)-triggered effector functions of T lymphocytes including the TCR-triggered FasL mRNA up-regulation in cytotoxic T lymphocytes. Strong evidence against the intracellular lymphotoxicity of Ado (and in support of the signaling model) is provided by abrogation of TCR-triggered growth inhibition in Ado-exposed T cells. The brief exposure to Ado was sufficient to observe inhibition of TCR-triggered effector functions. The “memory” of T cells to exposure to extAdo is best explained by sustained increases in cAMP. Selective agonist (CGS21680) and antagonist (ZM241385) of A2A adenosine receptor were used in functional assays and cDNA probes for different sybtypes of adenosine receptors were used in Northern blot studies. A2Areceptors are identified as the predominantly expressed subtype of Gs-coupled Ado receptors in T cells. The demonstration of cross-talk between the A2A receptors and TCR in both directions support the possible role of A2A receptors in mechanisms of extAdo-mediated immunosuppression in vivounder adenosine deaminase deficiency and hypoxic conditions in,e.g., solid tumors. Adenosine (Ado) 1The abbreviations used are: Ado, adenosine; 2-CADO, 2-chloroadenosine; ADA, adenosine deaminase; BLT, benzyloxycarbonyl-l-lysine thiobenzyl ester; CSC, 8-(3-chlorostiryl) caffeine; CTL, cytotoxic T lymphocyte; dbcAMP,N-6,2-O-dibutyryladenosine 3′,5′-cyclic monophosphate; ELISA, enzyme-linked immunosorbent assay; extAdo, extracellular adenosine; FasL, Fas ligand; FCS, fetal calf serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IL, interleukin; mAb, monoclonal antibody; NECA, 5-N-ethylcarboxamide adenosine; ORF, open reading frame; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase PCR; SCID, severe combined immunodeficiency; TCR, T cell receptor. 1The abbreviations used are: Ado, adenosine; 2-CADO, 2-chloroadenosine; ADA, adenosine deaminase; BLT, benzyloxycarbonyl-l-lysine thiobenzyl ester; CSC, 8-(3-chlorostiryl) caffeine; CTL, cytotoxic T lymphocyte; dbcAMP,N-6,2-O-dibutyryladenosine 3′,5′-cyclic monophosphate; ELISA, enzyme-linked immunosorbent assay; extAdo, extracellular adenosine; FasL, Fas ligand; FCS, fetal calf serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IL, interleukin; mAb, monoclonal antibody; NECA, 5-N-ethylcarboxamide adenosine; ORF, open reading frame; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase PCR; SCID, severe combined immunodeficiency; TCR, T cell receptor. has been implicated in pathogenesis of diseases (1Giblett E.R. 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Reynolds T. Blay J. Int. J. Cancer. 1994; 59: 854-855Crossref PubMed Scopus (69) Google Scholar). Accumulated Ado is believed to be lymphotoxic, and humans with inherited ADA deficiency (undetectable ADA activity) are ill and have severe combined immunodeficiency (SCID) (2Hershfield M.S. Mitchell B.S. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Molecular and Metabolic Basis of Inherited Disease. McGraw-Hill, New York1995: 1725-1768Google Scholar, 3Hirschhorn R. Clin. Immunol. Immunopathol. 1995; 76: S219-S227Crossref PubMed Scopus (52) Google Scholar, 4Blackburn M.R. Datta S.K. Wakamiya M. Vartabedian B.S. Kellems R.E. J. Biol. Chem. 1996; 271: 15203-15210Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). ADA SCID is currently explained by the accumulation of lymphotoxic intracellular deoxyATP (dATP) and/or of S-adenosyl homocysteine as the cause of direct lymphotoxicity leading to the depletion of lymphocytes (2Hershfield M.S. Mitchell B.S. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Molecular and Metabolic Basis of Inherited Disease. McGraw-Hill, New York1995: 1725-1768Google Scholar, 3Hirschhorn R. Clin. Immunol. Immunopathol. 1995; 76: S219-S227Crossref PubMed Scopus (52) Google Scholar, 4Blackburn M.R. Datta S.K. Wakamiya M. Vartabedian B.S. Kellems R.E. J. Biol. Chem. 1996; 271: 15203-15210Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 13Liu X. Kim C.N. Yang J. Jemmerson R. Wang X. Cell. 1996; 86: 147-157Abstract Full Text Full Text PDF PubMed Scopus (4405) Google Scholar). Alternative mechanism(s) of effects of Ado on lymphocytes, as well as the possibility that their inhibition may be due to extracellular Ado-mediated transmembrane signaling through Ado (purinergic) receptors (5Huang S. Koshiba M. Apasov S. Sitkovsky M. Blood. 1997; 90: 1600-1610Crossref PubMed Google Scholar, 6Apasov S. Koshiba M. Redegeld F. Sitkovsky M. Immunol. 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Rev. 1995; 146: 5-19Crossref PubMed Scopus (80) Google Scholar), the accumulation of extAdo due to insufficient or absent ADA or under hypoxic conditions results in increased signaling through Ado receptors on T cells and causes signaling is for the of signaling on the effector functions of T cells and the of expressed Ado receptors on T cells to be of the and mechanisms of ADA SCID is for the of the pathogenesis of this In of the effects of extAdo on T cells are in on the of cytotoxic T lymphocytes to with solid hypoxic conditions may to Ado accumulation (12Hoskin D.W. Reynolds T. Blay J. Int. J. Cancer. 1994; 59: 854-855Crossref PubMed Scopus (69) Google Scholar). of the effects of pharmacological agents also this in of mechanisms of T effector with the of to Ado and of the effects of extAdo under well In this we immunosuppression of peripheral T lymphocytes in may be explained by extracellular intracellular Ado-mediated inhibition of cell receptor and T and and the effects of Ado be explained by extAdo we that that exposure of T cells to extAdo results in inhibition of TCR-triggered evidence of “memory” of Ado effects in T cells. The of extAdo to T cells an intracellular of Ado A2A receptors are identified as predominantly expressed and are functional of the T effects of the were Selective A2A receptor agonist and A2A receptor antagonist were Selective A2A receptor antagonist was Linden of and monoclonal was as M. J.A. S. PubMed Scopus Google Scholar). and were and and thymocytes were PubMed Scopus Google Scholar) was with in and H. S. H. H. Int. Immunol. PubMed Scopus Google Scholar). cell and T cell were used as and cells for The was as H. S. H. T. T. H. S. H. 1994; Full Text PDF PubMed Scopus Google Scholar). The was by and with cells. were used the and were in with and cells as of T cell growth cell J. J. D. S. 79: PubMed Scopus Google Scholar) was to and used as of T was as H. M. R. Sitkovsky M. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). benzyloxycarbonyl-l-lysine thiobenzyl activity was as H. Sitkovsky M.V. J. Med. PubMed Scopus Google Scholar). the of was the of in with with or Ado of under cells were for of was with of BLT, in The was for and the was by of which was in The was by of and the was in to that was the as the as the not with the the is to the The of the was cells. were in and are as the of activity which was the the in the of the is the in the of the and T the of in the was T. H. S. S. J. Immunol. 1996; Google Scholar). cells were with of for and cells were with different of as to or Ado or Ado analogs in of with FCS, cells were for in were the of was as and T and In this the cells were used as cells are not and not by the of to receptors on cells results in and TCR of the which is by of the and the to that the cells to R.E. Redegeld F. Sitkovsky M.V. J. Immunol. Google Scholar, Sitkovsky M.V. and Scholar). were with or with extAdo with or was by the of and the cDNA was by the to the The FasL was with to and of open reading of FasL cDNA T. T. S. Cell. Full Text PDF PubMed Scopus Google Scholar). used were by The for of FasL and glyceraldehyde-3-phosphate mRNA by were the to the The of not show that of the cDNA not The was under conditions in that of the cDNA and of of were on and by The of was Molecular the of the The of were for in cDNA between of for cDNA were and of The cells was as and was mRNA The of was by Northern (5Huang S. Koshiba M. Apasov S. Sitkovsky M. Blood. 1997; 90: 1600-1610Crossref PubMed Google Scholar). The cDNA was and cells as The A2A was with to and of of A2A cDNA S. J. Immunol. 1994; Google Scholar). A2A cDNA was D. of and used as The effects of different of lymphocytes on their were tested by cells or with different of Ado analogs and/or to or of were the to the were in with The of extAdo on was tested by cells for or with in were and for in in with and was as of on cell growth inhibition and of cells H. M. R. Sitkovsky M. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar) was tested by cells for or with in in cells were for with and with of by an in the of The of in of was by including of and Sitkovsky M. and Scholar). is explained by cells due to the of and cytotoxic Sitkovsky M.V. and Scholar) and due to receptor J. Med. PubMed Scopus Google Scholar). are different mechanisms that have in the for TCR was to which of was to effects of of effector and cells and the of to to between and that of in inhibition of both and leading to and to of H. G. Sitkovsky M.V. J. Biol. Chem. 1988; Full Text PDF PubMed Google Scholar). in model we not extracellular signaling as of was to of be sufficient to cause the inhibition of functions signaling through Ado receptors in peripheral T cells and A2A or the of receptors K.A. van Galen P.J.M. Williams M. J. Med. Chem. 1992; 35: 407-422Crossref PubMed Scopus (501) Google Scholar). that the of Ado analogs TCR-triggered the demonstration of direct effects of extAdo analogs on in as was to and both and were in of of cytotoxic in by Ado was to in the inhibition of cell and this was by the of extAdo on cell by The used was to the as by the that cell is and was that of Ado in the cell not Ado also Ado analogs were and to Ado was as as and NECA, that Ado is for Selective A2A agonist concentrations as as also was to the of cells by this agonist was to be for A2A receptor Williams M. R. R. J. Med. Chem. 1990; PubMed Scopus Google Scholar). The of inhibition by was to that of extracellular adenosine and of concentrations of The to G. J. 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Cell. 1996; 86: 147-157Abstract Full Text Full Text PDF PubMed Scopus (4405) Google Scholar). were to the possibility that the in by Ado and may for the Ado-mediated inhibition of and In in of were detected not In this possibility is by results of of as concentrations (e.g. of extAdo of were and not the of and to inhibition by Ado, we of the of and and tested the of with that the of The cells used in the in were the of on the is that extAdo and Ado were to the of against the cells in by extAdo was as as Ado, with in inhibition of of inhibition of be due to inhibition of the of extAdo intracellular of cell in and/or inhibition of TCR-triggered FasL The was the of extAdo-mediated inhibition of cell in was to the of and cell in inhibition of the possibility of inhibition of cell we in which the cells were with In this the cell the TCR on the and are sufficient for both the and R.E. Redegeld F. Sitkovsky M.V. J. Immunol. Google Scholar, Sitkovsky M.V. and Scholar). In to normal cell are not for in we that extAdo of in not the was also to the possibility that inhibition of was due to the of extAdo of of cells. was in an as an to The cells, the cells that were used as with in were with H. S. H. T. T. H. S. H. 1994; Full Text PDF PubMed Scopus Google Scholar) in the or absence of extAdo or that both extAdo and were to have an on the in cells, the is also that extAdo and not have lymphotoxic on their not the that the inhibition of is due to the inhibition of TCR-triggered FasL to the of FasL on by due to insufficient of the not we the for FasL mRNA to the of extAdo on FasL in and The effects of extAdo on FasL mRNA in were tested by cells with with Ado or Ado and Ado for or In we used different to in of both FasL mRNA and of in the of this mRNA was as we that the mRNA of the be that of of in T lymphocytes M. Apasov S. Sitkovsky M.V. S. 1997; PubMed Scopus Google Scholar). the by of FasL mRNA were and of in the The of extAdo in inhibition of FasL mRNA in is that A2A receptor antagonist the extAdo-mediated inhibition of T cell FasL mRNA up-regulation the role of A2A receptors in effects of the of FasL mRNA in was in not Ado not effector as in was of T cells with and not The in were of the to possible due the to effects of extAdo and Ado analogs on cells. of Ado on of cells were not the that Ado with due to Ado-mediated signaling and not of the of In all of the effects of Ado were by of all tested TCR-triggered effector not the of cell of were by results are in with that Ado receptor signaling be the of the effects of increased concentrations of exposure to Ado was sufficient to TCR-triggered effector functions of T and T cells. were to with the effects of extAdo on lymphocytes in to the effects in due to possible of extAdo by ADA the of extAdo and as an lymphocyte be of the effects of extAdo be and be of Ado receptor signaling through increases in that increased of exposure to Ado and not considered the possible of of exposure to that of cells with extAdo or Ado by of Ado and of T cells in and in The was brief exposure to extAdo TCR-triggered T cell was that of T cells with for in inhibition of TCR-triggered as with in was sufficient to observe as as of exposure to extAdo in inhibition of TCR-triggered of results of an that the effects of extAdo to not inhibition of different effector functions also the of T cells TCR-triggered and inhibition of In we of the well of TCR-triggered signaling to cause the inhibition of T R.E. D. J. Med. PubMed Scopus Google Scholar). results of the effects of of exposure to extAdo is in yet assay; as as of exposure was sufficient to of T cells as with the of extAdo of T cell to is not with the intracellular lymphotoxicity model of Ado (2Hershfield M.S. Mitchell B.S. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Molecular and Metabolic Basis of Inherited Disease. McGraw-Hill, New York1995: 1725-1768Google Scholar, 3Hirschhorn R. Clin. Immunol. Immunopathol. 1995; 76: S219-S227Crossref PubMed Scopus (52) Google Scholar, 4Blackburn M.R. Datta S.K. Wakamiya M. Vartabedian B.S. Kellems R.E. J. Biol. Chem. 1996; 271: 15203-15210Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). is that extAdo reverse TCR signaling and inhibition of by and/or by the that inhibition of TCR-triggered effector functions of T cells is due to Ado signaling and we have that the increases in are sufficient to including H. G. Sitkovsky M.V. J. Biol. Chem. 1988; Full Text PDF PubMed Google Scholar), and is that the of exposure to extAdo is due to sustained in intracellular of cAMP. effects of Ado on thymocytes and on functions of and T cells were by an of or by the of H. G. Sitkovsky M.V. J. Biol. Chem. 1988; Full Text PDF PubMed Google Scholar), we considered the effects of extAdo on and T cells as due to increases in intracellular that are by Ado of thymocytes or of to extAdo or to Ado receptor in and sustained of intracellular the of The increased were for as as and to between the and of Ado, 2-CADO, and were all in accumulation and not and receptors as for the effects of extAdo in T cells. also show to K.A. M. PubMed Scopus Google Scholar), A2A receptors are predominantly expressed and in T cells were with in the or absence of CSC, and were The A2A receptor agonist K.A. M. PubMed Scopus Google Scholar) was to antagonist accumulation in were with and T cells and and not that role for receptors in T cells is The of A2A which has been in functional assays and of A2A is by Northern blot of and mRNA in T cells show that A2A receptor mRNA is predominantly expressed in T cells, and are not The of in mRNA used for and A2A receptor not and receptor was detected by Northern blot in thymocytes and T cells and not The Northern blot is the used of A2A mRNA was to of Ado receptors in of cells and to the of A2A receptor mRNA in The the Northern blot of A2A receptor mRNA in T cells and in the accumulation of was the of with of is by the results of with different of this by the of the and of in by of their with an of cells PubMed Scopus Google Scholar). not to the of TCR in of that the is due to cross-talk between TCR and Ado receptors in T cells. was by the results of in different T cells with Ado or with or to in cAMP. of T cells with in the of effects of T cell with were in and thymocytes was also detected with by was not between and cells were in this not the of extAdo signaling in thymocytes and was to in on the inhibition by was as as that of of inhibition by was the effects of were not not are of the used T cell in to tested cells, increased their in mAb, not to accumulation on T cells cells were different all T cells, the accumulation was of by in not with evidence of cross-talk between TCR-triggered and show that exposure of T lymphocytes to extAdo has effects and results in the inhibition of T cell effector functions effects of extAdo in assays are best explained by extAdo-mediated signaling through A2A Ado receptors and sustained increases in in TCR-triggered signaling The of A2A agonist to the of cells by the of A2A receptor as the predominantly expressed receptor in T lymphocytes. the of A2A adenosine receptor antagonist to the inhibition by and to extAdo-mediated inhibition of Fas up-regulation pharmacological evidence that effects of adenosine on functions are by signaling through A2A In (e.g. adenosine analogs were The inhibition of by is in with signaling effects of extAdo on T cells. that accumulation of is in the of may the of effects of adenosine on T cells by in of and The of cross-talk between A2A and TCR-triggered is in both as of T cells with extAdo the TCR-triggered and or of T cells with TCR in inhibition of signaling and accumulation The effects of receptor signaling on T cells are in with the large of on in T cells Immunol. 1988; Full Text PDF PubMed Scopus Google Scholar). is well by and that in H. M. R. Sitkovsky M. J. Biol. Chem. 1992; Full Text PDF PubMed Google H. G. Sitkovsky M.V. J. Biol. Chem. 1988; Full Text PDF PubMed Google Scholar) and in T cells Immunol. 1988; Full Text PDF PubMed Scopus Google Scholar) are to inhibition by the intracellular be that the of A2A receptor cross-talk in T cells on the of the T cells. In the were to inhibition by be of to in effects between different tested T cells in studies. T provided as of cells with in accumulation of the between and in T cells and between and T cells effects of TCR signaling on extAdo signaling may the in of between different of that were in the in to be with causes of A2A extAdo receptors or the of A2A receptors with transmembrane signaling in T cells. The TCR-triggered in A2A receptor an of T cell In with this we that of receptor mRNA in thymocytes the of M. Apasov S. Sitkovsky M.V. S. 1997; PubMed Scopus Google Scholar). the of mRNA be by or in this to that receptors in of of T cell M. Apasov S. Sitkovsky M.V. S. 1997; PubMed Scopus Google Scholar). exposure to extAdo was sufficient to TCR-triggered and by T cells The of exposure to extAdo by T cells is by sustained increases in exposure to and may the effects of ADA by the effects of of the effects of extAdo on lymphocytes in to effects in due to possible of extAdo by ADA The of T cells growth inhibition by as well as the or with extAdo, were in the in results to model in which Ado on T cells is due to intracellular is that the transmembrane signaling by extAdo and A2A lymphotoxicity of or are for growth effects of The of T cells is explained by an between TCR and extAdo is to increases in thymocytes (5Huang S. Koshiba M. Apasov S. Sitkovsky M. Blood. 1997; 90: 1600-1610Crossref PubMed Google Scholar, H. T. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar) and peripheral T cells (5Huang S. Koshiba M. Apasov S. Sitkovsky M. 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Koshiba et al. (Wed,) studied this question.