IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa

Blood. 2012 Sep 27;120(13):2610-9. doi: 10.1182/blood-2012-06-434779. Epub 2012 Aug 14.

Abstract

Interleukin-7 (IL-7) is a nonredundant cytokine that plays a critical role in T-cell homeostasis and promotes immunologic reconstitution in lymphopenic hosts. Here, we show that IL-7, at doses that reflect suprahomeostatic concentrations achieved in lymphopenic hosts, is a potent and selective inducer of the gut-homing integrin α4β7 in human T cells, as documented both ex vivo and in vivo in patients enrolled in a clinical trial of IL-7 treatment. Induction of α4β7 by IL-7 occurs primarily in naive T cells and is associated with functional activation of the integrin, as indicated by increased binding activity for the specific α4β7 ligand, MAdCAM-1. The physiologic relevance of these findings was validated by the preferential homing of IL-7-treated naive human T cells to the intestinal compartment in humanized NOD/SCID/IL-2 receptor-γ(null) (NSG) mice. We also show that IL-7 triggers a peculiar activation program in naive T cells, characterized by the acquisition of memory-like phenotypic features and proliferation uncoupled from expression of classic T-cell activation markers. These findings provide a mechanism for the transient in vivo depletion of circulating T cells after IL-7 administration and suggest that intestinal homing and memory-like conversion of naive T cells are critical steps in the IL-7-driven immunologic reconstitution of lymphopenic hosts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Animals
  • Blotting, Western
  • Cell Proliferation
  • Cytokines / metabolism
  • Flow Cytometry
  • HIV Infections / drug therapy
  • HIV Infections / metabolism*
  • HIV Infections / virology
  • HIV-1
  • Humans
  • Immunologic Memory
  • Integrins / metabolism*
  • Interleukin-7 / pharmacology*
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Receptors, Interleukin-2 / physiology*
  • Signal Transduction / drug effects
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism*

Substances

  • Cytokines
  • Integrins
  • Interleukin-7
  • Receptors, Interleukin-2
  • integrin alpha4beta7