Cell wall beta-1,2-oligomannosides are involved in Candida albicans binding to macrophages and in their stimulation to produce cytokines. The nature of signaling events occurring during initial interaction of macrophage J774 cell line and C. albicans, together with the nature of molecules containing beta-1,2-oligomannosides released by the yeasts, was examined. Cocultivation led to a herbimycin A-sensitive production of tumor necrosis factor-alpha. Immunofluorescence and Western blotting confirmed tyrosine phosphorylation and revealed an accumulation of 90- to 120-kDa phosphoproteins. Antibodies specific for beta-1,2-oligomannosides showed that these epitopes were shed at an early stage from the yeasts to the macrophage membrane, in association with a glycolipid previously described as C. albicans phospholipomannan. Incubation of macrophages with purified phospholipomannan alone led to a signal transduction pathway identical to that observed with living yeasts. All of these results demonstrate that C. albicans phospholipomannan shedding is involved in C. albicans-macrophage interaction through beta-1,2-oligomannosides.