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 the 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 leukocytes and on APCs. In addition to an adhesive function, ICAM-3 can act as 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 abrogated adhesion to LFA-1, including three residues that are located on strand A of the ABED face of domain 1. In contrast, extensive mutagenesis analysis of ICAM-1 has shown that only residues on the GFC face interact with LFA-1. Our results provide evidence for a more extensive binding interface between ICAM-3 and LFA-1 than has previously been described. ICAM-3 appears to be unique among the ICAMs in utilizing residues on both faces of domain 1 for interaction with its ligand LFA-1.