CROSS-LINKING OF ALPHA-4-BETA-1 AND ALPHA-5-BETA-1 FIBRONECTIN RECEPTORS ENHANCES NATURAL-KILLER-CELL CYTOTOXIC ACTIVITY

Cell/extracellular matrix interactions mediated by integrins regulate differentiation, migration, and effector functions of immune system co mponents. Human NK cells express alpha 4 beta 1 and alpha 5 beta 1 int egrins, which mediate their binding to fibronectin (FN). We have inves tigated the ability of FN and its beta 1 integrin receptors to modulat e NK cytotoxicity, Our data show that the presence of immobilized FN s ignificantly augments the spontaneous cytotoxic activity of in vitro c ultured human NK cells against several NK-susceptible, but not NK-resi stant, target cells; Ab-dependent cytotoxicity against Ab-coated P815 target cells and the redirected lysis of anti-CD16 hybridomas are also enhanced in the presence of FN. Solid-phase-bound anti-human beta 1, or its F(ab')(2) fragment, anti-alpha 4 and anti-alpha 5 mAbs, all con sistently enhance Ab-dependent cytotoxicity against Ab-coated murine t arget cells. The 120-kDa (alpha 5 beta 1-binding), but not the 40-kDa (alpha 4 beta 1-binding), FN fragment fully reproduced the enhancing e ffect observed with the entire molecule. Our data also demonstrate tha t alpha 4 beta 1 and alpha 5 beta 1 cross-linking on NK cells induces an increase of intracellular Ca2+ concentration that is abrogated by E GTA, thus suggesting that the capacity to mobilize Ca2+ is involved in the coactivating role of alpha 4 beta 1 and alpha 5 beta 1 FN recepto rs in the cytotoxic functions of NK cells.