A Single L/D-Substitution at Q4 of the mInsA_2-10 Epitope Prevents Type 1 Diabetes in Humanized NOD Mice.

ABSTRACT: 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_2-10DQ4 and mInsA_2-10DC6, respectively. We found that administration of mInsA_2-10DQ4, but not DC6, significantly suppressed the development of T1D in NOD.β2m^null .HHD mice. Mechanistically, treatment with mInsA_2-10DQ4 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.

SUBMITTER: Zhang M 

PROVIDER: S-EPMC8435724 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature