Monoclonal (IgG) antibodies (MAbs) directed to CD I6 molecules efficiently induced lysis of the IgG-binding P8 I 5 target cells. A similar effect was observed with selected anti-CD2 MAbs. While combinations of 2 appropriate anti-CD2 MAbs were required for induction of T lymphocyte activation, single stimulatory anti-CD2 MAbs were sufficient for inducing cytolytic function in CD3-CD16+ lymphocytes. In order to study possible regulatory mechanisms existing in the process of activation and induction of the cytolytic machinery of CD3-CD I6+ effector cells, we utilized the anti-CD I6 OKNK MAb. Being of IgM isotype, the OKNK MAb does not allow cross-linking between CD3-CD I6+ lymphocytes and target cells. Pre-treatment of effector cells with OKNK MAb sharply inhibited the target cell lysis induced by either antLCD16 (IgG) MAbs or stimulatory anti-CD2 MAb. Moreover, a strong inhibitory activity of PHA-induced target cell lysis and even of "spontaneous" lysis (at high effector:target ratio) was observed. In contrast, in CD3 CD16+ clones, OKNK MAb selectively inhibited the cell triggering induced by anti-CD I6 MAbs (but not by anti-CD3, anti-CD2 MAbs or PHA). Our data indicate that C D I 6 receptor molecules expressed by CD3-CD I6+ lymphocytes down-regulate cell responses to anti-CDZ MAbs or PHA, and then exert a regulatory role in the cytolytic function of these cells.