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Autoreactive CD8 +  T cells play an indispensable key role in the destruction of pancreatic islet β-cells and the initiation of type 1 diabetes (T1D). Insulin is an essential β-cell autoantigen in T1D. An HLA-A*0201-restricted epitope of insulin A chain (mInsA 2-10 ) is an immunodominant ligand for autoreactive CD8 +  T cells in NOD. β2m null  . HHD  mice. Altered peptide ligands (APLs) carrying amino acid substitutions at T cell receptor (TCR) contact positions within an epitope are potential to modulate autoimmune responses  via  triggering altered TCR signaling. Here, we used a molecular simulation strategy to guide the generation of APL candidates by substitution of L-amino acids with D-amino acids at potential TCR contact residues (positions 4 and 6) of mInsA 2-10 , named mInsA 2-10 DQ4 and mInsA 2-10 DC6, respectively. We found that administration of mInsA 2-10 DQ4, but not DC6, significantly suppressed the development of T1D in NOD. β2m null  . HHD  mice. Mechanistically, treatment with mInsA 2-10 DQ4 not only notably eliminated mInsA 2-10  autoreactive CD8 +  T cell responses but also prevented the infiltration of CD4 +  T and CD8 +  T cells, as well as the inflammatory responses in the pancreas of NOD. β2m null .HHD  mice. This study provides a new strategy for the development of APL vaccines for T1D prevention.

A Single L/D-Substitution at Q4 of the mInsA2-10 Epitope Prevents Type 1 Diabetes in Humanized NOD Mice