Studies were carried out to characterize the target cell for the activity of suppressor cells induced in highzone tolerance to deaggregated human gamma globulin (HGG). We applied an in vitro system for the initiation of an immune response, consisting of culturing spleen lymphocytes on HGG-fed macrophages, in which initiator T cells are generated. These cells, when injected into the foot pads of syngeneic mice, recruit specific anti-HGG effector T lymphocytes. We found that HGG-fed macrophages were incapable of signaling spleen cells from HGG-tolerant animals to generate initiator cells. Spleen cells from tolerant animals, when mixed with spleen cells from normal donors, inhibited the capacity of the normal population to give rise to initiator cells after culture on HGG-fed macrophages. Thus, suppressor T cells, which inhibit education of T cells by antigen-fed macrophages, exist in the tolerant spleen. Spleen cells from HGG-tolerant animals, when seeded on macrophages fed simultaneously with HGG and keyhole limpet hemocyanin (KLH), also prevented the macrophages from signaling an anti-KLH response. Spleen cells from HGG-tolerant animals from which the suppressor cells were depleted by “affinity chromatography” on histamine columns, when seeded on macrophages fed with HGG and KLH, generated initiators to both antigens. It appears, therefore, that suppressor cells act at the level of antigen-presenting macrophages, affecting macrophages fed with the tolerogen, and therefore affecting also the immunogenic effect of other antigens presented by the same macrophages. By testing the mode of action of suppressor cells on the tolerogen-fed macrophage, we found that the suppressors manifest a cytotoxic effect on such macrophages. We propose that the suppressor cell is, in fact, an anti modified-self killer, acting on macrophages possessing surface self-antigens “modified” by the tolerogen. The similarity in cell-surface markers between suppressors and anti modified-self killers supports this concept
