We analysed the mechanisms of T-cell unresponsiveness to Mycobacterium leprae antigens and to unrelated antigens or T-cell mitogens in human leprosy and in an experimental model of murine infection by M. lepraemurium (MLM). In human leprosy, monoclonal antibodies OKT3, OKT4 and OKT8 were used to enumerate T-cell subpopulations within peripheral blood. Increased percentages of OKT8+ cytotoxic/suppressor cells were observed in untreated, non-reactional lepromatous patients. Conversely, lepromatous patients suffering from erythema nodosum leprosum, an Arthus-like phenomenon, exhibited a transient drop in the percentage of OKT8+ cells with a correlative increase in the proliferative response to T-cell mitogens. We studied the proliferative response to M. leprae of OKT4+ and OKT8+ cells isolated by a negative selection procedure using antibody-induced cytotoxicity plus complement. None of these subpopulations proliferated when incubated with M. leprae. In some patients, control treatment of mononuclear cells with complement alone induced the reappearance of a strong proliferative response to M. leprae, suggesting the existence of an active suppressor mechanism through soluble factors of an unknown nature. In MLM-induced murine leprosy, a progressive decrease was observed in the proliferative response to concanavalin A (ConA), and an early decrease in interleukin 2 activity in supernatants from ConA-stimulated spleen cells. Splenic T cells from MLM-infected mice transferred into naive recipients accelerated the local MLM growth in these recipients, suggesting that suppressor T cells may play a pathogenic role in the progression of MLM infection.