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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. [Copyright &y& Elsevier]