Research ArticleAUTOIMMUNITY

How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes

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Science Immunology  05 Apr 2019:
Vol. 4, Issue 34, eaav7517
DOI: 10.1126/sciimmunol.aav7517

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Superagonist diabetogenic peptides

Type 1 diabetes is an autoimmune disease triggered, in part, by activation of CD4+ T cells specific for insulin-derived autoantigens. Wang et al. prepared ternary complexes of diabetogenic T cell receptors attached to ligands formed by binding of insulin B-chain peptides to mouse or human MHC class II proteins known to be associated with genetic susceptibility to diabetes. Structural and functional analyses revealed that fusion peptides featuring covalent linkage of the C terminus of an insulin B-chain peptide to specific fragments of insulin C-peptide were highly potent ligands, enabling avid binding of both mouse and human TCRs. These findings point to transpeptidation reactions in lysosomes as a potential source of superagonist chimeric insulin peptides with an important driver role in autoimmune diabetes.