Requirement for hla-dr + accessory cells in natural killing of cytomegalovirus-infected fibroblasts

Abstract

NK cells mediate spontaneous killing of tumor-derived cells, virus-infected cells, and certain normal cells (1, 2). This type of cytotoxicity does not require presensitization of the donor. For example, PBMC of individuals who are seronegative or seropositive for a given virus are equally able to lyse targets infected with that virus (3). Production of IFN by lymphocytes exposed to virusinfected target cells and subsequent stimulation of NK cells by IFN was originally proposed as the mechanism by which NK cells preferentially lyse virus-infected cells compared with uninfected ones (4). A primary role for IFN was challenged, however, by several authors who described a lack of correlation between magnitude of lysis and amounts of IFN detected in supernatant fluids (5, 6), an almost normal capacity of effector cells from patients with reduced ability to produce IFN to lyse virus-infected target cells (7), and the inability of anti-IFN antibodies when present during the NK assay to prevent lysis of virus-infected cells (5, 6). The cells responsible for NK activity against normal and tumor-derived target cell lines were identified as a leukocyte subset, distinct from B and T cells and from myelomonocytic cells (2). This subset expresses the low-affinity Fc receptor (FcR) 1 for aggregated IgG (CD16 antigen), recognized by a series of mAbs (8). NK cells responsible for lysis of virus-infected target cells have not been fully identified. Fitzgerald et al. (9) reported that the NK cells able to lyse HSVinfected targets differed from those that lysed K562 cells, as treatment of PBMC with an mAb to HLA-DR plus C reduced their ability to kill HSV-infected fibroblasts, but not K562 cells. These authors concluded that these NK cell subsets could be distinguished on the basis of surface expression of HLA-DR antigen. However, few if any resting NK (CD16+) cells in healthy donors are HLA-DR + (10, 1 1), raising the possibility that in the experiments of Fitzgerald et a]. (9), a HLA-DR +, non-NK cell population was depleted