LIGAND INTERCELLULAR-ADHESION MOLECULE-1 HAS A NECESSARY ROLE IN ACTIVATION OF INTEGRIN LYMPHOCYTE FUNCTION-ASSOCIATED MOLECULE-1

The signaling that causes the leukocyte integrin lymphocyte function-a ssociated molecule (LFA-1) to bind firmly to its ligand intercellular adhesion molecule 1 (ICAM-1) is transduced indirectly through other T- cell receptors and is termed inside-out signaling. We show here that t he high-affinity state of LFA-1 is characterized by expression of the LFA-1 epitope detected by monoclonal antibody 24. This epitope is expr essed not in response to the initial agonist-mediated signal but when LFA-1 binds to ICAM-1, indicating that ligand binding induces an alter ation in LFA-1. As would be predicted, the monoclonal antibody 24 epit ope is confined to the LFA-1, which is located at the site of contact between T cells and ICAM-1-expressing transfectants. When a fixation p rotocol for ''freezing'' receptors is used, only T cells that are fixe d after prior exposure to ICAM-1 bind firmly to ICAM-1 a second time. This suggests that, in addition to the inside-out signaling, a previou sly unrecognized requirement for full activation of the leukocyte inte grin LFA-1 is the initial interaction with its ligand ICAM-1. Thus, ac tivation of LFA-1 is in part achieved by an induced fit imposed from w ithout by interaction with ligand.