Selective inhibition of KCa3.1 channels mediates adenosine regulation of the motility of human T cells.
Adenosine, a purine nucleoside, is present at high concentrations in tumors, where it contributes to the failure of immune cells to eliminate cancer cells. The mechanisms responsible for the immunosuppressive properties of adenosine are not fully understood. We tested the hypothesis that adenosine's immunosuppressive functions in human T lymphocytes are in part mediated via modulation of ion channels. The activity of T lymphocytes relies on ion channels. KCa3.1 and Kv1.3 channels control cytokine release and, together with TRPM7, regulate T cell motility. Adenosine selectively inhibited KCa3.1, but not Kv1.3 and TRPM7, in activated human T cells. This effect of adenosine was mainly mediated by A2A receptors, as KCa3.1 inhibition was reversed by SCH58261 (selective A2A receptor antagonist), but not by MRS1754 (A2B receptor antagonist), and it was mimicked by the A2A receptor agonist CGS21680. Furthermore, it was mediated by the cAMP/protein kinase A isoform (PKAI) signaling pathway, as adenylyl-cyclase and PKAI inhibition prevented adenosine effect on KCa3.1. The functional implication of the effect of adenosine on KCa3.1 was determined by measuring T cell motility on ICAM-1 surfaces. Adenosine and CGS21680 inhibited T cell migration. Comparable effects were obtained by KCa3.1 blockade with TRAM-34. Furthermore, the effect of adenosine on cell migration was abolished by pre-exposure to TRAM-34. Additionally, adenosine suppresses IL-2 secretion via KCa3.1 inhibition. Our data indicate that adenosine inhibits KCa3.1 in human T cells via A2A receptor and PKAI, thereby resulting in decreased T cell motility and cytokine release. This mechanism is likely to contribute to decreased immune surveillance in solid tumors.
Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267.
Ameet A
AA
Chimote
Peter
P
Hajdu
Vladimir
V
Kucher
Nina
N
Boiko
Zerrin
Z
Kuras
Orsolya
O
Szilagyi
Yeo-Heung
YH
Yun
Laura
L
Conforti
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000037:antagonists & inhibitors / Q000502:physiology; D005260:Female; D006801:Humans; D007157:Immunologic Surveillance / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1; D007376:Interleukin-2 / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D017136:Ion Transport / Q000187:drug effects; D051664:Kv1.3 Potassium Channel / Q000502:physiology; D008213:Lymphocyte Activation; D008297:Male; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050053:TRPM Cation Channels / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D002121:Calcium Channel Blockers; D007376:Interleukin-2; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D051664:Kv1.3 Potassium Channel; D010627:Phenethylamines; D011720:Pyrazoles; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; C411671:TRAM 34; D050053:TRPM Cation Channels; D014230:Triazoles; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D018799:Intercellular Adhesion Molecule-1; D015124:8-Bromo Cyclic Adenosine Monophosphate; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D054743:Cyclic AMP-Dependent Protein Kinase Type I; D000241:Adenosine; D002118:Calcium