CD54 ICAM-1 IS A COSTIMULATOR OF NK CELL-MEDIATED CYTOTOXICITY/

The receptors and the array of cell adhesion molecules regulating MHC- unrestricted cytotoxic activity of NK cells toward tumor targets have not completely characterized. Antibody inhibition studies suggest role s for a number of cell adhesion molecules (CAMs). Recent studies sugge st that CAMs can function to stabilize cell-to-cell interactions and/o r to provide costimulatory signals that are crucial for T cell activat ion. It has been difficult to experimentally demonstrate that adhesion molecules also function as costimulators in NK cell-mediated cytotoxi city. We have developed an experimental system using cells transfected with genes encoding huICAM-1 and/or LFA-3 to investigate the function of adhesion molecules. Here we report that neither the expression of transfected ICAM-1 or LFA-3 alone nor the expression of both ICAM-1 an d LFA-3, in the absence of MHC class I molecules, converts a murine ce ll line that is resistant to NK cell-mediated lysis into a susceptible one. We next tested the ability of ICAM-1 or LFA-3-mediated interacti ons to provide costimulation of NK cell cytolytic activity using a ''t hree cell'' experimental system comprising human NK cells, C-51-labele d target cells, and transfected mouse cells as a source of costimulati on. The ability of NK cells to lyse K562 cells or anti-CD16-coated tar get cells was significantly enhanced by the addition of ICAM-1-transfe cted cells, whereas the addition of cells transfected with LFA-3 or ir relevant genes did not enhance lytic activity. Since the transfected h uICAM-1 interacts with NK cells at sites spatially separate from the N K cell-target cell interactions, our data suggest that LFA-1-ICAM-1 or MAC-1-ICAM-1 interactions can provide remote costimulation, via signa ling events, to induce cytotoxic activity in NK cells. (C) 1994 Academ ic Press, Inc.