MAdCAM-1 costimulates T cell proliferation exclusively through integrin alpha4beta7, whereas VCAM-1 and CS-1 peptide use alpha4beta1: evidence for "remote" costimulation and induction of hyperresponsiveness to B7 molecules

Eur J Immunol. 1998 Nov;28(11):3605-15. doi: 10.1002/(SICI)1521-4141(199811)28:11<3605::AID-IMMU3605>3.0.CO;2-J.

Abstract

We have analyzed the effects of the alpha4 integrin ligands mucosal addressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1), and the fibronectin CS-1 splice variant on T cell activation. Immobilized MAdCAM-1 and VCAM-1 IgG-Fc chimeras and a fibronectin CS-1 peptide efficiently costimulate T cell proliferation when antigen presentation is mimicked by anti-CD3 antibody. VCAM-1-Fc and fibronectin CS-1, which are adhesive ligands for both the alpha4beta1 and alpha4beta7 integrins, medicate T cell costimulation exclusively through integrin alpha4beta1, but not through alpha4beta7. The inability of VCAM-1-Fc to costimulate via alpha4beta7 suggests that cell adhesion per se is insufficient, and that exquisite recognition and activation events must be triggered. MAdCAM-1-Fc mediates costimulation exclusively via alpha4beta7, and can both synergize with and induce hyperresponsiveness to the classical costimulator B7-2. MAdCAM-1-Fc and VCAM-1-Fc, but not B7-2, effectively costimulate when immobilized on sites spatially distant from the anti-CD3 antibody ("remote" costimulation). In vitro, the relative potencies of the CAM were VCAM-1-Fc> ICAM-1-Fc> MAdCAM-1-Fc > B7-Fc, except at high concentrations where ICAM-1 was the most potent. Features of costimulatory CAM revealed by this study have important implications for the design of immunotherapeutic vaccine strategies to combat cancer and infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Adult
  • Amino Acid Sequence
  • Animals
  • Antigens, CD / physiology*
  • Antigens, Differentiation / physiology
  • B7-1 Antigen / physiology*
  • CTLA-4 Antigen
  • Cell Adhesion Molecules
  • Fibronectins / physiology*
  • Humans
  • Immunoconjugates*
  • Immunoglobulins / physiology*
  • Integrin alpha4
  • Interleukin-2 / metabolism
  • Lymphocyte Activation*
  • Mice
  • Molecular Sequence Data
  • Mucoproteins / physiology*
  • Rats
  • T-Lymphocytes / immunology*
  • Vascular Cell Adhesion Molecule-1 / physiology*

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • B7-1 Antigen
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cell Adhesion Molecules
  • Ctla4 protein, mouse
  • Ctla4 protein, rat
  • Fibronectins
  • Immunoconjugates
  • Immunoglobulins
  • Interleukin-2
  • MADCAM1 protein, human
  • Madcam1 protein, mouse
  • Madcam1 protein, rat
  • Mucoproteins
  • Vascular Cell Adhesion Molecule-1
  • Integrin alpha4
  • Abatacept