MADCAM-1 COSTIMULATES T-CELL PROLIFERATION EXCLUSIVELY THROUGH INTEGRIN ALPHA(4)BETA(7), WHEREAS VCAM-1 AND CS-1 PEPTIDE USE ALPHA(4)BETA(1) - EVIDENCE FOR REMOTE COSTIMULATION AND INDUCTION OF HYPERRESPONSIVENESS TO B7 MOLECULES

We have analyzed the effects of the alpha(4) integrin ligands mucosal addressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1), and the fibronectin CS-I splice variant on T cell activation. Immobilized MAdCAM-1 and VCAM-1 IgG-Fc, chimeras and a fi bronectin CS-I peptide efficiently costimulate T cell proliferation wh en antigen presentation is mimicked by anti-CD3 antibody. VCAM-1-Fc an d fibronectin CS-1, which are adhesive ligands for both the alpha(4)be ta(1) and alpha(4)beta(7) integrins, medicate T cell costimulation exc lusively through integrin alpha(4)beta(1) but not through alpha(4)beta (7). The inability of VCAM-1-Fc to costimulate via alpha(4)beta(7) sug gests that cell adhesion per se is insufficient, and that exquisite re cognition and activation events must be triggered. MAdCAM-1-Fc mediate s costimulation exclusively via alpha(4)beta(7) 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 wh en 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 conc entrations 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 infectio n.