The autologous mixed lymphocyte culture (AMLC) in humans has been reviewed. Normal human T cells are stimulated to proliferate in vitro when co-cultured with mitomycin-C-treated or X-irradiated autologous non-T-cells. This reactivity, termed autologous mixed lymphocyte reaction, is thought to represent a self-recognitive mechanism that might be important in regulating the cellular interactions involved in the generation of normal immune response. The nature of the stimulator cell remains a matter of controversy, with evidence suggesting that monocytes, B cells, or dendritic cells may be the major stimulatory populations. In addition, activated T cells expressing HLA-D/DR antigens are also capable of stimulating autologus T cells in AMLC. It was shown that treatment of stimulator cells with anti-HLA-DR antibodies resulted in a significant decrease in their stimulatory capacity in AMLC. These observations suggest that HLA-D/DR antigens, the human counterpart of murine Ia antigens coded for by the I-E subregion of the H-2 complex, expressed on non-T cells or activated T cells participate in the stimulation of AMLC. However, recent findings would suggest that HLA-DS, the human equivalent of murine I-A, is more important than HLA-DR in inducing proliferation in the AMLC. The nature of the T cell subpopulations stimulated by autologous non-T cells has not been clearly elucidated. Evidence has been presented to suggest that either helper T cells or suppressor T cells, as well as cytotoxic cells may be activated. Recent evidence involving the use of monoclonal antibodies that identify mutually exclusive T cell subsets suggests only T cells with the T4+ (helper/inducer) phenotype are triggered directly, but in the presence of such cells, T8+ (suppressor/cytotoxic) cells may also be activated. The T cells which respond in AMLC are a subset of the Con A-responsive T cell population and are separate from allogeneic MLC-responding T cells. Furthermore, the responding cells are T cells forming rosettes with autologous erythrocytes and have surface and functional characteristic of post-thymic precursors. Recent studies indicate that in AMLC between T and non-T cells or T and activated T cells phenotypically distinct subpopulations of T lymphocytes respond by proliferation and express distinct immunoregulatory function. Thus, it seems that distinct species of Ia antigens expressed on activated T cells as opposed to those expressed on non-T cells could participate in the triggering process for the stimulation of functionally distinct human T cell subpopulations.(ABSTRACT TRUNCATED AT 400 WORDS)