ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells

Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6198-203. doi: 10.1073/pnas.092576699.

Abstract

Endothelial cells (EC) play a central role in inflammatory immune responses and efficiently induce effector functions in T cells, despite lacking the classical costimulatory ligands CD80 and CD86. By using the mAb HIL-131 we now demonstrate that human inducible costimulator-ligand (ICOS-L), a molecule related to CD80/CD86, is constitutively expressed on human EC in vivo. In vitro, ICOS-L expression was strongly enhanced on human umbilical vein EC and microvascular EC by the inflammatory cytokines tumor necrosis factor alpha and IL-1beta, and to a lower extent by stimulation of EC by CD40 or lipopolysaccharide. Coculture of MHC class II(+) EC with resting memory CD4(+) T cells in the presence of superantigen led to a marked up-regulation of ICOS on T cells and to the production of Th1 (IFN-gamma, IL-2) and Th2 cytokines (IL-4, IL-10, IL-13). When these cocultures were performed in the presence of the inhibitory mAb HIL-131, secretion of all cytokines was reduced by about 50-80%, indicating that ICOS-L is a major costimulator in EC-mediated T cell activation. Taken together, our data suggest an important physiological role of ICOS-L in the reactivation of effector/memory T cells on the endothelium controlling the entry of immune cells into inflamed tissue.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Antibodies, Monoclonal / metabolism
  • Antigens, CD / biosynthesis
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis*
  • Antigens, Differentiation, T-Lymphocyte / physiology*
  • B7-1 Antigen / biosynthesis
  • B7-2 Antigen
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Division
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Endothelium, Vascular / cytology*
  • Flow Cytometry
  • Humans
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Interferon-gamma / biosynthesis
  • Interleukin-1 / metabolism
  • Interleukin-10 / biosynthesis
  • Interleukin-13 / biosynthesis
  • Interleukin-2 / biosynthesis
  • Interleukin-4 / biosynthesis
  • Ligands
  • Lipopolysaccharides / metabolism
  • Membrane Glycoproteins / biosynthesis
  • Mice
  • Mice, Inbred BALB C
  • Precipitin Tests
  • Protein Binding
  • Protein Biosynthesis*
  • Proteins / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / metabolism
  • Th1 Cells / metabolism*
  • Th2 Cells / metabolism*
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • B7-1 Antigen
  • B7-2 Antigen
  • CD86 protein, human
  • Cd86 protein, mouse
  • Cytokines
  • ICOS protein, human
  • ICOSLG protein, human
  • Icos protein, mouse
  • Icosl protein, mouse
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-1
  • Interleukin-13
  • Interleukin-2
  • Ligands
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Proteins
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-4
  • Interferon-gamma