INTERCELLULAR-ADHESION MOLECULE-3 IS THE PREDOMINANT COSTIMULATORY LIGAND FOR LEUKOCYTE FUNCTION ANTIGEN-1 ON HUMAN BLOOD DENDRITIC CELLS

Dendritic cells (DC) are potent stimulators of primary T lymphocyte re sponses to foreign antigen. The initial DC-T lymphocyte interaction in volves the binding of the adhesion molecule leukocyte function antigen -1 (LFA-1; CD11a/CD18) on the T lymphocyte to an intercellular adhesio n molecule (ICAM) on the DC. Although blood and tonsil DC express ICAM -1 (CD54) and 1CAM-2 (CD102) on their surface, anti-ICAM-1 and anti-IC AM-2 monoclonal antibodies (mAb) have little inhibitory activity on th e DC-stimulated mixed leukocyte reaction (MLR), We therefore examined the expression of the more recently identified LFA-1 ligand, 1CAM-3 (C D50), in comparison to ICAM-1 and ICAM-2 on blood DC and sought a func tional role for ICAM-3 in DC-mediated T lymphocyte responses. Resting blood DC expressed significantly more ICAM-3 than ICAM-1 or ICAM-2 as assessed by flow cytometry. Treatment of resting DC with interferon-ga mma led to increased expression of ICAM-1; however, ICAM-2 and ICAM-3 levels remained relatively constant. Solid-phase recombinant chimeric molecules ICAM-1-, ICAM-2- and ICAM-3-Fc were able to co-stimulate CD4 (+) T lymphocyte proliferation in conjunction with suboptimal solid-ph ase CD3 mAb 64.1. However, the anti-ICAM-3 mAb CAL 3.10 inhibited a DC -stimulated MLR to a greater extent than anti-ICAM-1 or anti-ICAM-2 re agents and appeared to act by blocking the DC ICAM-3-T lymphocyte LFA- 1 interaction. As ICAM-3 is the predominant LFA-1 ligand on resting bl ood DC, we postulate that DC may utilize ICAM-3 for initial DC- T lymp hocyte interactions, and that ICAM-1, which is up-regulated upon DC ac tivation, and/or ICAM-2, may contribute to DC migration or later phase s of the T lymphocyte activation process.