Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes

Use of an alternative open reading frame, potentially as a result of cellular stress, drives production of an unconventional insulin epitope that is recognized by cytotoxic T cells from individuals with type 1 diabetes; these T cells kill beta cells in vitro . Identification of epitopes that are recognized by diabetogenic T cells and cause selective beta cell destruction in type 1 diabetes (T1D) has focused on peptides originating from native beta cell proteins. Translational errors represent a major potential source of antigenic peptides to which central immune tolerance is lacking 1 , 2 . Here, we describe an alternative open reading frame within human insulin mRNA encoding a highly immunogenic polypeptide that is targeted by T cells in T1D patients. We show that cytotoxic T cells directed against the N-terminal peptide of this nonconventional product are present in the circulation of individuals diagnosed with T1D, and we provide direct evidence that such CD8 + T cells are capable of killing human beta cells and thereby may be diabetogenic. This study reveals a new source of nonconventional polypeptides that act as self-epitopes in clinical autoimmune disease.