Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells.
Adenosine, a purine nucleoside found at high levels in solid tumors, is able to suppress the recognition/adhesion and effector phases of killer lymphocyte-mediated tumor cell destruction. Here, we demonstrate that adenosine, at concentrations that are typically present in the extracellular fluid of solid tumors, exerts a profound inhibitory effect on the induction of mouse cytotoxic T cells, without substantially affecting T-cell viability. T-cell proliferation in response to mitogenic anti-CD3 antibody was impaired in the presence of 10 microM adenosine (plus coformycin to inhibit endogenous adenosine deaminase). Antigen-specific T-cell proliferation was similarly inhibited by adenosine. Anti-CD3-activated killer T (AK-T) cells induced in the presence of adenosine exhibited reduced major histocompatibility complex-unrestricted cytotoxicity against P815 mastocytoma cells in JAM and (51)Cr-release assays. Diminished tumoricidal activity correlated with reduced expression of mRNAs coding for granzyme B, perforin, Fas ligand and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), as well as with diminished Nalpha-CBZ-L-lysine thiobenzylester (BLT) esterase activity. Interleukin-2 and interferon-gamma synthesis by AK-T cells was also inhibited by adenosine. AK-T cells express mRNA coding for A(2A), A(2B) and A(3) receptors, but little or no mRNA coding for A(1) receptors. The inhibitory effect of adenosine on AK-T cell proliferation was blocked by an A(3) receptor antagonist (MRS1191) but not by an A(2) receptor antagonist (3,7-dimethyl-1-propargylxanthine [DMPX]). The A(3) receptor agonists (N(6)-2-(4-aminophenyl)ethyladenosine [APNEA] and N(6)-benzyl-5'-N-ethylcarboxamidoadenosine [N(6)-benzyl-NECA]) also inhibited AK-T cell proliferation. Adenosine, therefore, acts through an A(3) receptor to prevent AK-T cell induction. Tumor-associated adenosine may act through the same mechanism to impair the development of tumor-reactive T cells in cancer patients.
Hoskin
David W
DW
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. dwhoskin@is.dal.ca
Butler
Jared J
JJ
Drapeau
Dennis
D
Haeryfar
S M Mansour
SM
Blay
Jonathan
J
D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001921:Brain / Q000378:metabolism; D017252:CD3 Complex / Q000096:biosynthesis*; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D002860:Chromium Radioisotopes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger / Q000378:metabolism; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D013778:Tetrazolium Salts / Q000494:pharmacology; D013805:Theobromine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D017252:CD3 Complex; D002860:Chromium Radioisotopes; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D053221:TNF-Related Apoptosis-Inducing Ligand; D013778:Tetrazolium Salts; D013844:Thiazoles; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C057837:3,7-dimethyl-1-propargylxanthine; D007371:Interferon-gamma; D000243:Adenosine Deaminase; C022616:thiazolyl blue; D000241:Adenosine; D013805:Theobromine; D013936:Thymidine