Distinct functions of surface receptors in the induction of neutrophil-mediated cytotoxicity.

Abstract

The respective roles of cell surface receptors were studied in a model of cell-mediated cytotoxicity using 51Cr-labelled chicken erythrocytes as target cells and human polymorphonuclear neutrophils (PMN) as effector cells. The attachment of the targets to PMN, demonstrated by rosette formation, was achieved by PMN surface receptors for C3 or for Fc IgG. No receptors for Fc IgM could be demonstrated. Direct contact between targets and effector cells was required and no cell-free cytotoxic mediator was demonstrable in this model. Target cells bound to PMN-C3 receptors were not lysed unless a cytotoxicity inducing signal was delivered. This was provided by anti-PMN heteroantibodies, or by their F(ab')2 fragments as well. It was therefore possible to trigger the cytotoxic reaction by bypassing PMN-surface receptors for Fc IgG. When the target cells are coated with IgG antibodies, PMN receptors for Fc IgG ensure both the attachment and the triggering signal for the cytotoxic reaction. Polymorphonuclear neutrophils (PMN) have been reported to the effective killer cells in vitro under three different experimental conditions: during phagocytosis, in the presence of antibody directed against the target cells and in the presence of lectins. PMN accumulation has also been considered as a major component of the pathogenesis of many forms of immunologic tissue injuries since PMN may react with immune complexes bound to a surface which they cannot phagocytose. Under these circumstances, they release lysosomial enzymes, by a mechanism which has been called "reverse endocytosis" or "frustrated phagocytosis". Attachment of PMN to target involves cell surface receptors (Fc gamma R) for the Fc region of the IgG molecule and/or receptors (C3R) for the activated third component of complement. The binding of aggregated or antigen-complexed IgG to PMN surface Fc gamma R generates signals triggering the internalization phase of phagocytosis, the antibody-dependent cell cytotoxicity (ADCC) and the stimulation of glucose oxidation by the hexose monophosphate pathway. However, the latter metabolic activation was also reported to be triggered by the fixation of antibodies specific for PMN surface determinants. It was therefore conceivable that modifications induced at the membrane level on any structure distinct from Fc gamma R would produce metabolic changes leading to target cell destruction, provided that a close contact could be established between effector and target cells. In the present study we have investigated the respective roles of Fc gamma R, C3R and other yet undefined surface determinants of PMN in the induction of cytotoxic activity towards heterologous target cells.