Interleukin 10 (IL-10) is a cytokine with a variety of reported effects including inhibition of monocyte major histocompatibility complex (MHC) class II-dependent antigen presentation, type 1 helper T cell cytokine production, and inhibition of T cell proliferation. Herein we report the effect of IL-10 pretreatment on antigen presentation to tumor- and allo-specific CD8+ cytotoxic T lymphocytes (CTL). Prior incubation of human melanoma cells with recombinant IL-10 (rIL-10) for 48-72 h resulted in a dose-dependent, up to 100% inhibition, of autologous CTL-mediated, HLA-A2.1-restricted, tumor-specific lysis. Allo-specific CTL cytotoxicity against Epstein-Barr virus-transformed lymphoblastoid cell lines (LCL) was also inhibited, demonstrating a protective effect also on lymphoid cells. In contrast, IL-10 pretreatment of allogeneic LCL or K562 targets had either no effect or slightly enhanced cytotoxic activity mediated by freshly isolated or IL-2-activated natural killer cells. Flow cytometric analysis with monoclonal antibodies against HLA-A2, or nonpolymorphic determinants of MHC class I proteins, revealed a 20-50% reduction in cell-surface expression, whereas intercellular adhesion molecules 1, and 2, and lymphocyte function-associated antigen 3 levels were not affected. In addition, relative to untreated target cells, IL-10 pretreated tumor cells were unaltered in their capacity to affect CTL-mediated lysis by cold target inhibition, demonstrating that the effect of IL-10 is unrelated to the initial binding of CTL to their targets. These results are compatible with an effect of IL-10 on the MHC class I antigen presentation pathway, and suggest a novel mechanism of immune tolerance, based on escape from CTL-mediated tumor and allo-transplant rejection.