A late, prolonged activation of the phosphatidylinositol 3-kinase pathway is required for T cell proliferation.
Activation of the phosphatidylinositol-3 kinase (PI 3-K) pathway is associated with the proliferation of many cell types, including T lymphocytes. However, recent studies in cell lines stably expressing deletion mutants of IL-2R that fail to activate PI 3-K have questioned the requirement for this pathway in cell cycle regulation. In this study with IL-2 and IL-7, we show in primary T cells that, unlike IL-2, IL-7 fails to induce the early activation of PI 3-K seen within minutes and normally associated with cytokine signaling. However, kinetic experiments showed that both of these T cell growth factors induce a distinct and sustained phase of PI 3-K activity several hours after stimulation. This delayed activation correlates with cell cycle induction and from studies using inhibitors of PI 3-K signaling, we show that this later phase, unlike the early activation within minutes, is required for cell cycle induction. The data presented here will have major implications for our understanding of the mechanism of T cell proliferation as well as the regulation of PI 3-K activity.
Lali
Ferdinand V
FV
Kennedy Institute of Rheumatology Division, Imperial College London, UK.
Crawley
James
J
McCulloch
Derek A
DA
Foxwell
Brian M J
BM
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000502:physiology; D015851:Interleukin-7 / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D002867:Chromones; D019927:Cyclin E; D003513:Cycloheximide; D006131:Growth Inhibitors; D007093:Imidazoles; D007376:Interleukin-2; D015851:Interleukin-7; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D016160:Retinoblastoma Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580