Induction of proliferation and NK activity in human lymphocytes by mature myelomonocytic cells: evidence for an HLA-DR-independent MLR stimulatory ability of terminally differentiated nonlymphoid leukemic cell lines and of normal peripheral blood granulocytes

Abstract

Three human myeloid leukemic cell lines (HL60, KG1, and ML3) and one histiocytic lymphoma line (U937) were induced to differentiate terminally to mature myelomonocytic cells with either 12-O-tetradecanoylphorbol-13-acetate (TPA) or lymphocyte-conditioned medium (LCM), which is known to contain differentiation-inducing factors. HL60 cells were also forced to differentiate along the myeloid series with retinoic acid (RA) or dimethyl sulfoxide (DMSO). The striking morphologic changes and the expression of differentiated markers on the induced cells (whether macrophage- or granulocyte-like) were always associated with an acquired or dramatically increased ability to stimulate proliferation and natural killer cell (NK) activity in human lymphocytes. Like HL60 cells after granulocytic differentiation, granulocytes freshly separated from the peripheral blood of healthy donors were also strong inducers of mixed lymphocyte reaction (MLR) responses. Analysis of the expression of HLA-DR antigens on the surface of undifferentiated and mature cells with two monoclonal antibodies directed against HLA-DR monomorphic determinants, indicated that 1) upon differentiation induced with RA, DMSO, and TPA the cells never acquired surface DR antigens, and 2) normal peripheral blood granulocytes lacked these antigens. In contrast, treatment with LCM always resulted in the expression of high levels of DR antigens on the differentiated macrophage-like cells. Taken together, these findings indicate that all mature myelomonocytic cells, either freshly separated from peripheral blood or obtained after forced in vitro differentiation of leukemic cells, express MLR stimulatory antigens that appear to be unrelated to DR determinants. The possibilities discussed are that such antigens are associated with other molecules encoded by the D region or with new surface structures unrelated to Ia but dependent on the stage of differentiation.