Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells

David W. Hoskin, Jared J. Butler, Dennis Drapeau, S. M.Mansour Haeryfar, Jonathan Blay

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

69 Citas (Scopus)

Resumen

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 μM 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 51Cr-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 Nα-CBZ-L-lysine thiobenzylester (BLT) esterase activity. Interleukin-2 and interferon-γ synthesis by AK-T cells was also inhibited by adenosine. AK-T cells express mRNA coding for A2A, A2B and A3 receptors, but little or no mRNA coding for A1 receptors. The inhibitory effect of adenosine on AK-T cell proliferation was blocked by an A3 receptor antagonist (MRSI191) but not by an A2 receptor antagonist (3,7-dimethyl-1-propargylxanthine [DMPX]). The A3 receptor agonists (N6-2-(4-aminophenyl)ethyladenosine [APNEA] and N6-benzyl-5′N-ethylcarboxamidoadenosine [N6-benzyl-NECA]) also inhibited AK-T cell proliferation. Adenosine, therefore, acts through an A3 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.

Idioma originalEnglish
Páginas (desde-hasta)386-395
Número de páginas10
PublicaciónInternational Journal of Cancer
Volumen99
N.º3
DOI
EstadoPublished - may. 20 2002

ASJC Scopus Subject Areas

  • Oncology
  • Cancer Research

Huella

Profundice en los temas de investigación de 'Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells'. En conjunto forman una huella única.

Citar esto