Interactions between CTL and target cells occur in the absence of specific antigen recognition and precede subsequent interaction of the TCR with its specific antigen. This antigen-independent adhesion progresses through two different pathways, one involving the interaction of CD2 with LFA-3 on the target cell, the second the interaction of LFA-1 with ICAM-1. Such antigen-independent adhesions are critical for the activation of T cells via the TCR. Also, CD4 and CD8 can serve as adhesion molecules by binding to monomorphic determinants expressed on class II and class I MHC antigens, respectively, on the target cells, but compared to LFA-1 and CD2 antigens their contribution to conjugate formation is minor. CD4 and CD8 are required for effective T-cell activation in situations where the intrinsic affinity of the TCR or antigen expression is low, suggesting that CD4 and CD8 enhance the avidity of T cells for target cells by binding to class II and class I antigen, respectively. However, CD4 and CD8 are also involved in post-binding events that lead to CTL activation and subsequent lysis of the target cells. On the other hand, blocking of anti-TCR/CD3 mAb-induced CTL reactivity by anti-CD4/CD8 mAbs does not necessarily involve an interference with the binding of CD4 and CD8 to their respective ligands and it has been proposed that the TCR and CD4 or CD8 form functional complexes that are required for optimal T-cell activation. It is still unclear whether blocking by anti-CD4/CD8 mAbs is based on the prevention of complex formation of the TCR with CD4 or CD8, since formation of such complexes has yet to be demonstrated. The alternative hypothesis, that anti-CD4/anti-CD8 mAbs can directly confer negative regulatory signals to the CTL is not supported by our studies with antibody-directed lysis mediated by a CD4+, CD8+ CTL clone. Anti-CD4/CD8 mAbs can also inhibit T-cell cytotoxicity induced by other T-cell surface activation antigens such as CD2 or Tp103. In these situations, the triggering may involve signals transferred via CD3 requiring functional CD3/CD8 or CD3/CD4 complexes. Although most studies investigating the sequence of events leading to T-cell activation are carried out with CTL, preliminary data indicate that the same mechanisms described here for CTL activation are probably also valid for the interactions of T-helper cells with APC or B cells.(ABSTRACT TRUNCATED AT 400 WORDS)