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Autoreactive CD8 + T cells, which play an indispensable role in β cell destruction, represent an emerging target for the prevention of type 1 diabetes (T1D). Altered peptide ligands (APLs) can efficiently induce antigen-specific T cells anergy, apoptosis or shifts in the immune response. Here, we found that HLA-A*0201-restricted CD8 + T cell responses against a primary β-cell autoantigen insulin epitope InsB1 5-14 were present in both NOD.β2m null .HHD NOD mice and T1D patients. We generated several APL candidates for InsB1 5  -14 by residue substitution at the p6 position. Only H6F exhibited an inhibitory effect on mInsB1 5-  14 -specific CD8 + T cell responses in vitro. H6F treatment significantly reduced the T1D incidence, which was accompanied by diminished autoreactive CD8 + T cell responses to mInsB1 5-14 , inhibited infiltration of CD8 + and CD4 + T cells in the pancreas and reduced pro-inflammatory cytokine production in pancreatic and splenic T cells in NOD.β2m null .HHD mice. Mechanistically, H6F treatment significantly augmented a tiny portion of CD8 + CD25 + Foxp3 + T cells in the spleen and especially in the pancreas. This subset exhibited typical Treg phenotypes and required peptide-specific restimulation to exert immunosuppressive activity. Therefore, this APL H6F may be a promising candidate with potential clinical application value for antigen-specific prevention of T1D.

An altered CD8+ T cell epitope of insulin prevents type 1 diabetes in humanized NOD mice