Sustained B7/CD28 interactions and resultant phosphatidylinositol 3-kinase activity maintain G1-->S phase transitions at an optimal rate.
Twenty-four hours of TCR engagement and CD28 costimulation was found sufficient to elicit an optimal rate of cell division over a 72-h period only when a high concentration of IL-2 was produced in the culture and remained readily available to the CD4(+) T cells. The cell division response could be aborted following 24 h of stimulation by the simultaneous abrogation of IL-2R signaling and the blockade of CD28 or TCR ligands. Biochemical and pharmacologic studies indicated that a phosphatidylinositol 3-kinase-Akt signaling cascade costimulated by the TCR and CD28 maintained the blasting cell division rate at a maximal level beyond 24 h even when IL-2 was withdrawn, neutralized, or exhausted. These data show that CD4(+) T cells remain sensitive to antigens (Ag) and costimulatory signals throughout the clonal expansion response. Furthermore, only those T cells that perceive the presence of a continued threat in the form of Ag/MHC complexes and B7 costimulatory ligands or a high concentration of a growth factor are directed to remain in cell cycle.
Bonnevier
Jody L
JL
Rheumatic and Autoimmune Diseases Division and Center for Immunology, University of Minnesota Medical School, Minneapolis, 55455, USA.
Yarke
Cory A
CA
Mueller
Daniel L
DL
D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D048708:Cell Growth Processes / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase / Q000276:immunology / Q000502:physiology*; D007376:Interleukin-2 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011494:Protein Kinases / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016196:S Phase / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D018122:B7-1 Antigen; D018106:CD28 Antigens; D016572:Cyclosporine; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D011948:Receptors, Antigen, T-Cell; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse