Graft-vs.-leukemia (GVL) is postulated to be the principal mechanism responsible for continued remission after allogeneic bone marrow transplantation (BMT). The specific cytotoxic effectors mediating this effect are as yet undefined, but the major histocompatibility complex (MHC)-nonrestricted lysis of tumor cell lines by natural killer (NK) and lymphokine-activated killer (LAK) cells from recipients of allogeneic BMTs has been proposed as an in vitro correlate of GVL. In vitro culture or treatment in vivo with interleukin-2 (IL-2) is associated with enhanced NK cytotoxicity and lysis of NK-resistant targets (LAK cytotoxicity). NK, LAK, and cytotoxic T lymphocytes (CTL) have cytotoxic properties against autologous and allogeneic leukemic targets. These immune effector cells require receptor-ligand interaction for target recognition and adhesion via specific molecules such as integrins, a group of heterodimeric transmembrane glycoproteins. The integrins include the very late activation (VLA) subfamily, which all share the same beta 1 subunit but have distinct chains. VLA-6 (CDw49f) has been identified on NK cells and binds to laminin, a basement membrane protein found on malignant tumor cells but not normal cells. Monoclonal antibodies (mAbs) to laminin have been found to inhibit in vitro cytotoxicity of the tumor cell line K562, suggesting an important role for VLA-6 in this interaction. The specific aim of this study was to investigate the role of VLA-6 in the interactions of the tumor cell lines K562 and Daudi with peripheral blood lymphocytes (PBL) acting as effectors in cell-mediated cytotoxicity from normal volunteers, patients recovering from chemotherapy, and patients recovering from autologous or allogeneic BMT. In over 96% of assays, incubation of effector cells with anti-CDw49f mAbs led to detectable inhibition of NK and LAK cell-mediated cytotoxicity. More notably, the degree of anti-VLA6-induced suppression of LAK activity was significantly greater in the normal donors than in any of the patient groups, despite a significantly lower incidence of expression of VLA-6 on NK cells from controls than from patients. This implies a reduced role for this adhesion molecule in LAK activity following some form of in vivo stimulation. This hypothesis is supported by the observation that addition of exogenous IL-2 to the cultures ameliorated the effect of VLA-6 blockade, although the incidence and level of VLA-6 expression was unchanged by IL-2. In contrast, VLA-6 blocking led to a greater reduction in NK activity of BMT recipients than of normal donors, demonstrating that the VLA-6 adhesion pathway is important in this group of patients. These results indicate that the VLA-6-laminin interaction is important in normal NK-target interaction but may play a less significant role in the innate cytotoxic response post-BMT, perhaps reflecting subtle differences in the subsets of NK cells present in BMT recipients compared with normal donors.