Gangliosides, immunosuppressive molecules shed by tumor cells, are potent inhibitors of monocyte accessory cell function. However, the specific monocyte cellular defect caused by gangliosides is unknown. Here we sought to delineate whether this abnormality is in the induction of suppressor cells, in intracellular antigen processing, or in intercellular antigen presentation. Three sets of studies of the tetanus toxoid (TT)-induced lymphoproliferative response, which is dependent upon monocyte accessory function, address this issue: (1) Antigen (TT)-primed human monocytes incubated with 50-100 microM human brain gangliosides for 24-48 h, washed, and then combined with T-cells, were inhibited in triggering T-cell proliferation, showing that the effect was occurring after antigen processing was complete. (2) T-cell responses to immobilized anti-CD3 or to antigen-primed control monocytes in the presence of ganglioside-exposed monocytes were unaffected, showing that ganglioside-exposed monocytes did not act as suppressor cells. (3) Stimulation by TT peptide fragment 830-843, which does not require processing, was completely inhibited by exposure of monocytes to gangliosides. These findings identify ganglioside interference with monocyte accessory cell function at the level of antigen presentation. We conclude that tumor gangliosides may inhibit host anti-tumor cellular immune responses by preventing the effective cellular interactions of the antigen-primed monocyte with the responding T-lymphocyte.