CD46 downregulation by measles virus (MV) occurs after expression of virus haemagglutinin (H) protein on the surface of the infected cell and is a consequence of CD46-H interaction on the cell membrane. To assess whether CD46 downregulation also occurs after CD46-H interaction when these two molecules are expressed on distinct cells, we used human T cell line Jurkat (expressing CD46) and transfected murine fibroblast line L stably expressing MV-H protein (L.H). FACS analysis shows that cell-to-cell contact of 1 h at 37 degrees C triggers a reduction of CD46 cell surface labelling as detected by MCI20.6, GB24 and J4-48 monoclonal antibodies. This reduction is similar to that observed after MV infection or after infection with recombinant vaccinia virus encoding MV-H protein. By contrast, MV-H protein was downregulated only when CD46-H interaction occurred on the same cell membrane. CD46 downregulation is specific for CD46-H interaction because it was not observed after coincubation of Jurkat cells with either L cells expressing MV nucleoprotein (L.NP) or L cells. Moreover, this downregulation could be blocked by either anti-CD46 or anti-H antibodies. The H-mediated CD46 downregulation is reversible and restricted to CD46 since expression of other surface markers (CD3, CD14, CD47 and CD63) is unaffected. It is apparently not mediated in a protein kinase (PK) A- or PKC-dependent manner. Altogether, our results provide an unequivocal demonstration that interaction between the extracellular domains of CD46 and MV-H is sufficient to trigger CD46 downregulation.