Abstract
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. 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.
Original language | English |
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Pages (from-to) | 501-507 |
Number of pages | 7 |
Journal | Nature Medicine |
Volume | 23 |
Issue number | 4 |
DOIs | |
Publication status | Published - Apr 2017 |
Keywords
- Adolescent
- Adult
- Autoantigens
- Autoimmunity
- CD8-Positive T-Lymphocytes
- Child
- Dendritic Cells
- Diabetes Mellitus, Type 1
- Female
- HLA-DQ Antigens
- Humans
- Immunohistochemistry
- Insulin
- Insulin-Secreting Cells
- Male
- Open Reading Frames
- Peptides
- Protein Biosynthesis
- RNA, Messenger
- T-Lymphocytes, Cytotoxic
- Young Adult
- Journal Article