THE ALPHA-4 INTEGRIN CHAIN IS A LIGAND FOR ALPHA-4-BETA-7 AND ALPHA-4-BETA-1

The heterodimeric alpha 4 integrins alpha 4 beta 7 lymphocyte Peyer's patch adhesion molecule ([LPAM]-1) and alpha 4 beta 1 (very late antig en-4) are cell surface adhesion molecules involved in lymphocyte traff icking and lymphocyte-cell and matrix interactions. Known cellular lig ands include vascular cell adhesion molecule (VCAM)-1, which binds to alpha 4 beta 1 and alpha 4 beta 7, and the mucosal addressin cell adhe sion molecule (MAdCAM)-1, which binds to alpha 4 beta 7. Here we show that the alpha 4 chain of these integrins can itself serve as a ligand . The alpha 4 chain, immunoaffinity purified and immobilized on glass slides, binds thymocytes and T lymphocytes. Binding exhibits divalent cation requirements and temperature sensitivity which are characterist ic of integrin-mediated interactions, and is specifically inhibited by anti-alpha 4 integrin antibodies, which exert their effect at the cel l surface. Cells expressing exclusively alpha 4 beta 7 (TK-1) or alpha 4 beta 1 (L1-2) both bound avidly, whereas alpha 4-negative cells did not. A soluble 34-kD alpha 4 chain fragment retained binding activity , and it inhibited lymphocyte adhesion to alpha 4 ligands. It has been shown that alpha 4 integrin binding to fibronectin involves an leucin e-aspartic acid-valine (LDV) motif in the HepII/IIICS region of fibron ectin (CS-1 peptide), and homologous sequences are important in bindin g to VCAM-1 and MAdCAM-1. Three conserved LDV motifs occur in the extr acellular sequence of alpha 4. A synthetic LDV-containing alpha 4-deri ved oligopeptide supports alpha 4-integrin-dependent lymphocyte adhesi on and blocks binding to the 34-kD alpha 4 chain fragment. Our results suggest that alpha 4 beta 7 and alpha 4 beta 1 integrins may be able to bind to the alpha 4 subunit on adjacent cells, providing a novel me chanism for alpha 4 integrin-mediated and activation-regulated lymphoc yte interactions during immune responses.