INTERLEUKIN-10 PRETREATMENT PROTECTS TARGET-CELLS FROM TUMOR-SPECIFICAND ALLO-SPECIFIC CYTOTOXIC T-CELLS AND DOWN-REGULATES HLA CLASS-I EXPRESSION

Interleukin 10 (IL-10) is a cytokine with a variety of reported effect s including inhibition of monocyte major histocompatibility complex (M HC) class II-dependent antigen presentation, type 1 helper T cell cyto kine production, and inhibition of T cell proliferation. Herein we rep ort the effect of IL-10 pretreatment on antigen presentation to tumor- and allo-specific CD8(+) cytotoxic T lymphocytes (CTL). Prior incubat ion 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 C TL-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 effec t also on lymphoid cells. In contrast, IL-10 pretreatment of allogenei c LCL or K562 targets had either no effect or slightly enhanced cytoto xic activity mediated by freshly isolated or IL-2-activated natural ki ller cells. Flow cytometric analysis with monoclonal antibodies agains t HLA-A2, or nonpolymorphic determinants of MHC class I proteins, reve aled a 20-50% reduction in cell-surface expression, whereas intercellu lar adhesion molecules 1, and 2, and lymphocyte function-associated an tigen 3 levels were not affected. In addition, relative to untreated t arget cells, IL-10 pretreated tumor cells were unaltered in their capa city to affect CTL-mediated lysis by cold target inhibition, demonstra ting that the effect of IL-10 is unrelated to the initial binding of C TL to their targets. These results are compatible with an effect of IL -10 on the MHC class I antigen presentation pathway, and suggest a nov el mechanism of immune tolerance, based on escape from CTL-mediated tu mor and allo-transplant rejection.