THE CD8 glycoprotein of T cells binds nonpolymorphic regions of class I major histocompatibility complex proteins on target cells1,2 and these interactions promote antigen recognition and signalling by the T-cell receptor3-11. Studies using artificial membranes indicated that effective CD8/class I interaction is critical for response by alloantigen-specific cytotoxic T lymphocytes when class I protein is the only ligand on the antigen-bearing surface10,11. But significant CD8-mediated binding of cytotoxic T lymphocytes to non-antigenic class I protein could not be detected in the absence of the alloantigen12. These apparently contradictory findings indicate that CD8 binding to class I protein might be activated through the T-cell receptor and the results reported here demonstrate that this is the case. Treatment of cytotoxic T lymphocytes with soluble anti-T-cell receptor antibody activates adhesion of the cytotoxic T lymphocytes to class I, but not class II proteins. The specificity of this binding implies that it is mediated by CD8 and blocking by anti-CD8 antibodies confirmed this. Furthermore, binding of CD8 to class I protein resulted in generation of an additional signal(s) necessary to initiate response at low T-cell receptor occupancy levels.