Differential control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and pyrimidine nucleotides.
Purine and pyrimidine nucleotides play critical roles in DNA and RNA synthesis as well as in membrane lipid biosynthesis and protein glycosylation. They are necessary for the development and survival of mature T lymphocytes. Activation of T lymphocytes is associated with an increase of purine and pyrimidine pools. However, the question of how purine vs pyrimidine nucleotides regulate proliferation, cell cycle, and survival of primary T lymphocytes following activation has not yet been specifically addressed. This was investigated in the present study by using well-known purine (mycophenolic acid, 6-mercaptopurine) and pyrimidine (methotrexate, 5-fluorouracil) inhibitors, which are used in neoplastic diseases or as immunosuppressive agents. The effect of these inhibitors was analyzed according to their time of addition with respect to the initiation of mitogenic activation. We showed that synthesis of both purine and pyrimidine nucleotides is required for T cell proliferation. However, purine and pyrimidine nucleotides differentially regulate the cell cycle since purines control both G(1) to S phase transition and progression through the S phase, whereas pyrimidines only control progression from early to intermediate S phase. Furthermore, inhibition of pyrimidine synthesis induces apoptosis whatever the time of inhibitor addition whereas inhibition of purine nucleotides induces apoptosis only when applied to already cycling T cells, suggesting that both purine and pyrimidine nucleotides are required for survival of cells committed into S phase. These findings reveal a hitherto unknown role of purine and pyrimidine de novo synthesis in regulating cell cycle progression and maintaining survival of activated T lymphocytes.
Laboratoire d'immunopharmacologie, Institut National de la Santé et de la Recherche Médicale Unité 503, Centre d'Etudes et de Recherche en Virologie et Immunologie, Institut Fédératif de Recherche 128 Biosciences Lyon-Gerland, France.
Laurence
L
Quéméneur
Luc-Marie
LM
Gerland
Monique
M
Flacher
Martine
M
Ffrench
Jean-Pierre
JP
Revillard
Laurent
L
Genestier
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002449:Cell Aggregation / Q000187:drug effects / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016193:G1 Phase / Q000187:drug effects / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011685:Purine Nucleotides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology*; D011742:Pyrimidine Nucleotides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000276:immunology; D016196:S Phase / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D006131:Growth Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D011685:Purine Nucleotides; D011742:Pyrimidine Nucleotides