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

Blood. 2007 Feb 1;109(3):1034-42. doi: 10.1182/blood-2006-06-027912. Epub 2006 Oct 5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Glucose Transporter Type 1
  • Interleukin-7
  • Phosphatidylinositol 3-Kinases