IL-7-induced proliferation of recent thymic emigrants requires activation of the PI3K pathway

Swainson, L.; Kinet, S.; Mongellaz, C.; Sourisseau, M.; Henriques, T.; Taylor, N.


2007-02-01 / vol 109 / pages 1034-42


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.

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Humans; Signal Transduction; Dose-Response Relationship, Drug; Cell Survival/drug effects; Cell Cycle/drug effects; *Cell Movement; 1-Phosphatidylinositol 3-Kinase/*metabolism; Cell Proliferation/*drug effects; Glucose Transporter Type 1/analysis/drug effects; Interleukin-7/*pharmacology; T-Lymphocytes/cytology; Thymus Gland/*cytology

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