One of the mechanisms ensuring immunological unresponsiveness or tolerance depends on the action of CD8 + lymphocytes. In this paper, we report that, in healthy subjects, a subset of CD8 + CD28 - T cells suppresses the specific response to TSH receptor (TSHR) of CD4 + clones. Suppression was highly specific, required cell-cell interaction, and was not mediated by cytotoxicity. Co-incubation of CD8 + and CD4 + clones, followed by the removal of the CD8 + cells from the cultures before testing CD4 + responsiveness to TSHR, demonstrated that CD4 + cells were anergic since they showed low response to the antigen and a significant impairment of IL-2 production. In CD8-mediated anergy induction, the T-cell receptor (TCR) on both CD4 + and CD8 + cells seems to play a role. Our results indicate that one of the mechanisms ensuring peripheral tolerance involve CD8 + CD28 - cells. A disregulation in the control of autoreactive clones by this subset might be important for the onset of autoimmune thyroid diseases.