IL-7-induced proliferation of recent thymic emigrants requires activation of the PI3K pathway.
The IL-7 cytokine promotes the survival of a diverse T-cell pool, thereby ensuring an efficient immune response. Moreover, IL-7 induces the proliferation of recent thymic emigrants (RTEs) in neonates. Here, we demonstrate that the survival and proliferative effects of IL-7 on human RTEs can be distinguished on the basis of dose as well as duration of IL-7 administration. A dose of 0.1 ng/mL IL-7 is sufficient to promote viability, whereas cell-cycle entry is observed only at doses higher than 1 ng/mL. Moreover, a short 1-hour exposure to high-dose IL-7 (10 ng/mL) induces long-term survival but continuous IL-7 exposure is necessary for optimal cell-cycle entry and proliferation. We find that distinct signaling intermediates are activated under conditions of IL-7-induced survival and proliferation; STAT5 tyrosine phosphorylation does not correlate with proliferation, whereas up-regulation of the glucose transporter Glut-1 as well as increased glucose uptake are markers of IL-7-induced cell cycle entry. Glut-1 is directly regulated by PI3K and, indeed, inhibiting PI3K activity abrogates IL-7-induced proliferation. Our finding that the survival and proliferation of RTEs are differentially modulated by the dose and kinetics of exogenous IL-7 has important implications for the clinical use of this cytokine.
Swainson
Louise
L
Institut de Génétique Moléculaire de Montpellier, France.
Kinet
Sandrina
S
Mongellaz
Cedric
C
Sourisseau
Marion
M
Henriques
Telmo
T
Taylor
Naomi
N
D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D051272:Glucose Transporter Type 1 / Q000032:analysis / Q000187:drug effects; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology*
D051272:Glucose Transporter Type 1; D015851:Interleukin-7; D019869:Phosphatidylinositol 3-Kinases