Relative roles of T-cell receptor ligands and interleukin-2 in driving T-cell proliferation.
Stimulation of T cells by the T-cell receptor (TCR)/CD3 complex results in interleukin-2 (IL-2) synthesis and surface expression of the IL-2 receptor (IL-2R), which in turn drive T-cell proliferation. However, the significance of the requirement of IL-2 in driving T-cell proliferation, when TCR stimulation itself delivers potential mitogenic signals, is unclear. We show that blocking of IL-2 synthesis by Cyclosporin A (CsA) suppressed both the Concanavalin A (Con A)- and phorbol myristate acetate (PMA)/ionomycin-induced proliferation of T cells. The latter is also inhibited by anti-IL-2R. Kinetic studies showed that T-cell proliferation begins to become resistant to CsA inhibition by about 12 h and became largely resistant by 18 h of stimulation. PMA, the protein kinase C activator, enhanced Con A-induced T-cell proliferation if added only within first 12 h of stimulation, and not after that. Given the fact that, in the present study, TCR is downregulated within 2 h of Con A stimulation and T cells entered the S phase of cell cycle by about 18 h of stimulation, the above results suggest that TCR stimulation provides the initial trigger to the resting T cells, which allows the cells to traverse the first two third portions of G1 phase of cell cycle and become proliferation competent. IL-2 action begins afterward, delivering the actual proliferation signal(s), allowing the cells to traverse the rest of G1 phase and enter the S phase of the cell cycle.
Chakrabarti
R
R
Molecular Biology Unit, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
Kumar
S
S
Chakrabarti
R
R
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D003208:Concanavalin A / Q000494:pharmacology; D016193:G1 Phase; D007376:Interleukin-2 / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D011493:Protein Kinase C / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000378:metabolism*; D016196:S Phase; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*
D007376:Interleukin-2; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D003208:Concanavalin A; D011493:Protein Kinase C