IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa.
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.
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Raffaello
R
Cimbro
Lia
L
Vassena
James
J
Arthos
Claudia
C
Cicala
John H
JH
Kehrl
Chung
C
Park
Irini
I
Sereti
Michael M
MM
Lederman
Anthony S
AS
Fauci
Paolo
P
Lusso
D000328:Adult; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D015497:HIV-1; D006801:Humans; D007156:Immunologic Memory; D016023:Integrins / Q000378:metabolism*; D015851:Interleukin-7 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
D016207:Cytokines; D016023:Integrins; D015851:Interleukin-7; D015375:Receptors, Interleukin-2; C071777:integrin alpha4beta7