INTERCELLULAR-ADHESION MOLECULE-1 DIMERIZATION AND ITS CONSEQUENCES FOR ADHESION MEDIATED BY LYMPHOCYTE FUNCTION ASSOCIATED-1

Intercellular adhesion molecule-1 (ICAM-1, CD54) is a ligand for the i ntegrins lymphocyte function associated-1 (LFA-1, CD11a/CD18) and comp lement receptor-3 (Mac-1, CD11b/CD18) making it an important participa nt in many immune and inflammatory processes. Modified recombinant sol uble ICAM-1 formed dimers. This result indicated that the ectodomain o f ICAM-1 contains hemophilic interaction sites. Soluble ICAM-1 dimers bind to solid-phase purified LFA-1 with high avidity (dissociation con stant [K-d] = 8 nM) in contrast to soluble ICAM-1 monomers whose bindi ng was not measurable. Cell surface ICAM-1 was found to be dimeric bas ed on two distinct criteria. First, a monoclonal antibody specific for monomeric soluble ICAM-1, CA7, binds normal ICAM-1 poorly at the cell surface; this antibody, however, binds strongly to two mutant forms o f ICAM-1 when expressed at the cell surface, thus identifying elements required for dimer formation. Second, chemical cross-linking of cell surface ICAM-1 on transfected cells and tumor necrosis factor-activate d endothelial cells results in conversion of a portion of ICAM-1 to a covalent dimer. Cell surface ICAM-1 dimers are more potent ligands for LFA-l-dependent adhesion than ICAM-1 monomers. While many extracellul ar matrix-associated ligands of integrins are multimeric, this is the first evidence of specific, functionally important homodimerization of a cell surface integrin ligand.