THE LEUKOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 (LFA-1)-BINDING SITE ON ICAM-3 COMPRISES RESIDUES ON BOTH FACES OF THE FIRST IMMUNOGLOBULIN DOMAIN

ICAM-3 (CD50), a member of the Ig superfamily, is a major ligand for t he leukocyte integrin LFA-1 (CD11a/CD18), This interaction represents one of several Ig superfamily/integrin ligand-receptor pairs that have been described to date. ICAM-3 is highly expressed on resting leukocy tes and on APCs, In addition to an adhesive function, ICAM-3 can act a s a signal-transducing molecule on T cells, providing a costimulatory signal for cell proliferation. Eighteen point mutations in ICAM-3 were generated, and residues important for binding of functional blocking Abs were identified. Mutation of seven of the residues reduced or abro gated adhesion to LFA-1, including three residues that are located on strand A of the ABED face of domain 1, In contrast, extensive mutagene sis analysis of ICAM-1 has shown that only residues on the GFC face in teract with LFA-1, Our results provide evidence for a more extensive b inding interface between ICAM-3 and LFA-1 than has previously been des cribed. ICAM-3 appears to be unique among the ICAMs in utilizing resid ues on both faces of domain 1 for interaction with its ligand LFA-1.