SIGNALING THROUGH THE LFA-1 LEUKOCYTE INTEGRIN ACTIVELY REGULATES INTERCELLULAR-ADHESION AND TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION IN NATURAL-KILLER-CELLS

The LFA-1 leucocyte integrin is known to participate in natural killer (NK) cytolytic activity, mediating effector target interactions. The possibility that LFA- 1 may also play an active regulatory role in NK cells has been explored. To this end, we have employed a monoclonal an tibody (HP1N) raised against recombinant interleukin-2 (rIL-2)-activat ed NK cells, which recognizes the alpha chain of the LFA-1 heterodimer (CD11a). In contrast to other anti-CD11a mAb the HP1N and its F(ab')2 fragment did not affect NK cell-mediated cytotoxicity and triggered a strong homotypic adhesion of NK cells and other LFA-1 + cells. Cellul ar aggregation was inhibited by anti-CD18 mAb, anti-ICAM-1 mAb, and ot her anti-CD11a mAb. Remarkably, the HP1N mAb was also shown to induce tumor necrosis factor-alpha (TNF-alpha) production from NK cells upon costimulation with anti-CD16 mAb. Such an effect appeared to be indepe ndent from homotypic adhesion since it took place in Mg2+-free medium, where NK cell aggregation was inhibited. Moreover, incubation with the HP1N mAb triggered a Ca+ influx into the cytosol; this effect was cle arly observed upon cross-linking of cell bound HP1N and was also subst antiated with other anti LFA-1 (CD11a and CD18) mAb. Taken together th ese results indicate that the LFA-1 molecule is capable of transducing signals in NK cells, which regulate the intercellular interaction wit h its ligand, and enhance the activation via Fcgamma receptor type III .