The initiation of a specific immune response is believed to require not only activation through antigen-specific receptors on T cells and B cells but also antigen-independent interactions between accessory molecules. One such molecule is LFA-1, which enhances the avidity of interactions between T cells and antigen-presenting cells, and is possibly involved in signal transduction across the T-cell membrane. Intercellular adhesion molecule-1 (ICAM-1), a surface glycoprotein of relative molecular mass (Mr) 80,000-110,000, has been defined as a ligand for LFA-1, and has been shown to participate in the interaction between T cells and monocytes. The determination of the precise contribution of such accessory molecules to antigen presentation, however, is complicated by the need to analyse against a background of multiple molecular interactions. We have investigated the role of LFA-1/ICAM-1 interactions in antigen presentation directly by quantifying the contribution of ICAM-1 expression to T-cell stimulation using L-cell transfectants that co-express ICAM-1 and HLA-DR. In the case of transfectants expressing modest levels of HLA-DR, co-expression of ICAM-1 is critical for effective HLA class II-restricted and allospecific T-cell activation, pointing to an important role for ICAM-1 in the induction of T-cell responses.