title: Cross-linking of alpha 4 beta 1 and alpha 5 beta 1 fibronectin receptors enhances natural killer cell cytotoxic activity.
abstract: Cell/extracellular matrix interactions mediated by integrins regulate differentiation, migration, and effector functions of immune system components. Human NK cells express alpha 4 beta 1 and alpha 5 beta 1 integrins, which mediate their binding to fibronectin (FN). We have investigated the ability of FN and its beta 1 integrin receptors to modulate NK cytotoxicity. Our data show that the presence of immobilized FN significantly augments the spontaneous cytotoxic activity of in vitro cultured human NK cells against several NK-susceptible, but not NK-resistant, 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 consistently enhance Ab-dependent cytotoxicity against Ab-coated murine target 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 effect observed with the entire molecule. Our data also demonstrate that 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 EGTA, 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 receptors in the cytotoxic functions of NK cells.
authors.affiliation: Department of Experimental Medicine, University La Sapienza, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Palmieri
authors.forename: A
authors.initials: A
authors.lastname: Serra
authors.forename: R
authors.initials: R
authors.lastname: De Maria
authors.forename: A
authors.initials: A
authors.lastname: Gismondi
authors.forename: M
authors.initials: M
authors.lastname: Milella
authors.forename: M
authors.initials: M
authors.lastname: Piccoli
authors.forename: L
authors.initials: L
authors.lastname: Frati
authors.forename: A
authors.initials: A
authors.lastname: Santoni
mesh_terms: D000911:Antibodies, Monoclonal; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D005353:Fibronectins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism / Q000494:pharmacology; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D017469:Receptors, Fibronectin / Q000378:metabolism*; D017452:Receptors, IgG / Q000502:physiology; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D005353:Fibronectins; D007140:Immunoglobulin Fab Fragments; D039041:Integrin alpha4beta1; D016023:Integrins; D017469:Receptors, Fibronectin; D017452:Receptors, IgG; D016201:Receptors, Lymphocyte Homing; D002118:Calcium