We have been studying human T-cell clones that suppress anti-mycobacterial T-cell responses but not T-cell responses to an unrelated antigen or mitogen. In the present paper we report our studies on the activation requirements of these suppressor-T-cell clones. The suppressor-T-cell clones could proliferate and produce interferon-gamma upon stimulation with Mycobacterium leprae and other mycobacteria but not with unrelated antigens or autologous T cells. Both suppressor and nonsuppressor clones react to a 36-kDa antigen of M. leprae. Thus far, we have not been able to demonstrate whether they see the same or different epitopes. The antigen-driven proliferation of suppressor-T-cell clones was, however, significantly lower than that observed for T-cell clones that did not mediate suppression. The proliferation of suppressor-T-cell clones to M. leprae antigens could be blocked by monoclonal antibodies to HLA-DR, alpha beta T-cell receptor, interleukin-2 receptor, and, in the case of CD4-positive suppressor-T-cell clones, anti-CD4 monoclonal antibodies. DR restriction of the antigen presentation to these suppressor-T-cell clones was shown in mixing experiments using antigen-presenting cells as mononuclear cells from family members and unrelated individuals. These experiments also indicated that apart from regular DR-restriction a hitherto unknown factor may be required for presentation to or activation of suppressor-T-cell clones that is present in the family members and unrelated individuals with the same ethnic and geographic background but absent in DR/Dw-matched healthy Dutch individuals.