The structure recognized by regulatory T cells that enables them to discriminate self from nonself in the periphery is one of the central issues of regulatory T cell biology. A link between immunoregulation and self–nonself discrimination has emerged from experiments showing that Qa-1-restricted CD8⁺ T cells selectively down-regulate target T cells activated by the intermediate avidity of their own T cell antigen receptor–ligand interactions. Because the peripheral self-reactive T cell repertoire is devoid of high-avidity T cells compared with the foreign-reactive repertoire, as a result of thymic negative selection, the selective down-regulation of intermediate but not high-avidity T cells enables the immune system to suppress autoimmunity without damaging the ongoing immune response to foreign pathogens. However, the molecular mechanism delineating how avidity of T cell activation is perceived by the regulatory T cells has not been elucidated. Here we show that a heat shock peptide (Hsp60sp), coupled with the MHC class Ib molecule Qa-1, is a surrogate target structure that is preferentially expressed at a higher level on the intermediate avidity T cells and specifically recognized by the Qa-1-restricted CD8⁺ T cells. The biological significance of this observation was confirmed by the ability of Hsp60sp-loaded relevant dendritic cells to induce a Qa-1-restricted CD8⁺ T cell-mediated protection from autoimmune encephalopathy in the experimental allergic encephalomyelitis model. Thus, perceiving the avidity of T cell activation can be translated into peripheral T cell regulation to discriminate self from nonself in the periphery to maintain self-tolerance.