AbstractPurified OKT8+but not OKT4+T lymphocytes generated suppressor activity in autologous mixed lymphocyte reactions (AMLR) in the presence but not in the absence of interleukin 2 (IL 2) as determined in proliferative responses of peripheral blood mononuclear cells induced by Concanavalin A, the OKT3 monoclonal antibody and allogeneic cells (indicator systems for suppressor activity used in this study). Furthermore, treatment of AMLR‐activated T cells with the OKT8 antibody plus complement abolished suppressor cell activity whereas treatment of the cells with the OKT4 antibody plus complement did not.The three monoclonal anti‐HLA‐DR antibodies used in this study abrogated the induction, but not the effector phase, of suppressor cells in AMLR. The anti‐DR antibodies acted specifically on the stimulator non‐T cells and not on the responder T cells. The addition of IL2 to AMLR cultures performed in the presence of the anti‐DR antibodies did not restore or increase the suppressor activity whereas IL2 added to AMLR cultures exposed to control antibodies or medium alone increased the suppressor activity. Moreover, purified OKT8+T cells cocultured with autologous non‐T cells and IL2, in the presence of the anti‐DR antibodies, neither responded to IL2 by proliferating nor expressed suppressor function. In contrast, OKT8+T cells from similar cultures, but performed in the absence of the anti‐DR antibodies or exposed to control antibodies, proliferated to IL2 stimulation and exhibited suppressor activity. Unactivated OKT8+T cells were unresponsive to IL2 and unable to express suppressor function. Finally, the addition of the OKT8 antibody (in the absence of complement) to AMLR cultures had no effect on the generation of suppressor cells.From these results, we conclude the following: (a) OKT8+T lymphocytes become sensitive to IL2 by interacting with HLA‐DR antigens on the stimulator non‐T cells and, with the help of IL2, they express suppressor cell activity; (b) the OKT8 antigenic determinant on AMLR‐activated suppressor cells does not seem to participate in their process of activation; (c) results of previous studies showing that OKT4+T lymphocytes become sensitive to IL1 and are capable of synthesizing IL2 after interaction with HLA‐DR on the stimulator cells, and the findings presented here, lead us to suggest that both OKT4+and OKT8+T lymphocytes possess receptors for self HLA‐DR antigens and that neither the OKT8 nor the OKT4 antigenic determinants on these cells are involved in the recognition of HLA‐DR antigens. The suppressor activity generated in AMLR may be one mechanism whereby effector self‐tolerance is maintained in the fac