A key feature of the immune system is its ability to discriminate self from nonself. Breakdown in any of the mechanisms that maintain unresponsiveness to self (a state known as self-tolerance) contributes to the development of autoimmune conditions. Recent studies in mice show that CD8 + T cells specific for the unconventional MHC class I molecule Qa-1 bound to peptides derived from the signal sequence of Hsp60 (Hsp60sp) contribute to self/nonself discrimination. However, it is unclear whether they exist in humans and play a role in human autoimmune diseases. Here we have shown that CD8 + T cells specific for Hsp60sp bound to HLA-E (the human homolog of Qa-1) exist and play an important role in maintaining peripheral self-tolerance by discriminating self from nonself in humans. Furthermore, in the majority of type 1 diabetes (T1D) patients tested, there was a specific defect in CD8 + T cell recognition of HLA-E/Hsp60sp, which was associated with failure of self/nonself discrimination. However, the defect in the CD8 + T cells from most of the T1D patients tested could be corrected in vitro by exposure to autologous immature DCs loaded with the Hsp60sp peptide. These data suggest that HLA-E-restricted CD8 + T cells may play an important role in keeping self-reactive T cells in check. Thus, correction of this defect could be a potentially effective and safe approach in the therapy of T1D.

It was recently shown that perceiving the avidity of T cell activation can be translated into peripheral T cell regulation to control autoimmune disease. This regulation is achieved by CD8 ؉ T cells that recognize a common surrogate target structure, Qa-1/Hsp60sp, preferentially expressed by activated T cells of intermediate but not high avidity. A truncated self-reactive repertoire, devoid of high-avidity T cells, generated by thymic negative selection, allows selective downregulation of intermediate-avidity T cells to accomplish self-nonself discrimination in the periphery. Identification of the common surrogate target structure expressed on intermediate-avidity T cells opens up a conceptual theme to understand the relationship between the specificity of peripheral immune regulation and self-nonself discrimination. Here, we investigated peptide vaccination induced crossprotection mediated by CD8 ؉ T cells in two autoimmune disease models, experimental allergic encephalomyelitis (EAE) and type 1 diabetes (T1D). We show that Qa-1 restricted CD8 ؉ T cells crossprotect animals from either EAE or T1D without abrogating the immune response to foreign antigens. Cross-protection occurs because potentially pathogenic self-reactive T cells included in the pool of intermediate-avidity T cells are capable of preferentially expressing common surrogate target structures on their surface to render themselves subject to the down-regulation, independent of the specificity of the antigens that they are triggered by. Thus, like in the thymus, the immune system discriminates self from nonself, during adaptive immunity in the periphery, not by recognizing the structural differences between self and foreign antigens, but rather by perceiving the avidity of T cell activation.avidity model ͉ Qa-1/HLA-E-restricted CD8 ϩ T cells ͉ Qa-1/Hsp60sp ͉ autoimmune disease ͉ cross-protection