Secretion of IL-2 and IFN-gamma, but not IL-4, by antigen-specific T cells requires extracellular ATP.
Extracellular ATP and other nucleotides transmit signals to cells via surface-associated molecules whose binding sites face the extracellular milieu. Ecto-nucleoside triphosphate diphosphohydrolase is such an ATP-binding enzyme that is expressed by activated lymphocytes. We have previously shown that nonhydrolyzable ATP analogs block the lytic activity of NK cells and CD8(+) T cells as well as their E-NTPDase activity. These results suggest that the hydrolysis of ATP may play a role in lymphocyte function. Here we report that E-NTPDase activity is up-regulated within 15 min of T cell stimulation and that reversible and irreversible enzyme inhibitors profoundly reduce secretion of IL-2 and IFN-gamma, but not IL-4. TNF-alpha, IL-10, and IL-5 production showed intermediate sensitivity to these ATP analogs. Depletion of extracellular ATP also inhibited secretion of IFN-gamma, but not IL-4, supporting the interpretation that extracellular ATP is required for secretion of some, but not all, cytokines. E-NTPDase antagonists reduced transcription of IL-2 mRNA and inhibited TCR-mediated intracellular calcium flux. These results suggest that extracellular ATP plays an essential role in the TCR-mediated signal transduction cascade for expression of certain cytokine genes.
Langston
Heather P
HP
Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Ke
Yong
Y
Gewirtz
Andrew T
AT
Dombrowski
Kenneth E
KE
Kapp
Judith A
JA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD; D001081:Apyrase / Q000378:metabolism; D001665:Binding Sites / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006825:Hybridomas; D007371:Interferon-gamma / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D007399:Interphase / Q000276:immunology; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*
D015703:Antigens, CD; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D015847:Interleukin-4; C022571:adenosine 5'-O-(3-thiotriphosphate); C010959:5'-(4-fluorosulfonylbenzoyl)adenosine; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C027201:ectoATPase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine; D002118:Calcium