In the thymus there are two major mechanisms of T-lymphocyte tolerance: clonal deletion and clonal inactivation. One important problem underlying the mechanism of clonal inactivation is why unresponsive cells are maintained in the mature peripheral T-cell repertoire. Here we report that transgenic alpha beta T-cells may be tolerized to a self antigen Mls-1a, but still retain proliferative responses for alternative peptide antigens and superantigens. These self-tolerant T cells can also provide immunopathological and memory cytotoxic function in vivo. We propose that high-affinity/avidity self-reactive T cells are deleted in the thymus, whereas lower-affinity/avidity interactions lead to unresponsiveness and define the 'resting threshold' for a given T cell. These low-affinity self-tolerant T cells remain functionally competent for high-affinity foreign antigens, and efficiently eliminate natural pathogens in vivo.