Journal
SCIENCE
Volume 351, Issue 6274, Pages 711-714Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aad2791
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Funding
- NIH [1K01DK094941, 1R01DK081166, 5U01DK89572, DK104211]
- American Diabetes Association [1-15-ACE-14, 1-15-JF-04]
- Australian National Health and Medical Research Council (NHMRC) [APP1061961]
- Juvenile Diabetes Research Foundation [5-CDA2014210-A-N, 2-SRA-2015-68-Q-R]
- Victorian State Government of Australia
- Helmsley Charitable Trust [2015PG-T1D057]
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T cell-mediated destruction of insulin-producing beta cells in the pancreas causes type 1 diabetes T1D). CD4 T cell responses play a central role in beta cell destruction, but the identity of the epitopes recognized by pathogenic CD4 T cells remains unknown. We found that diabetes-inducing CD4 T cell clones isolated from nonobese diabetic mice recognize epitopes formed by covalent cross-linking of proinsulin peptides to other peptides present in beta cell secretory granules. These hybrid insulin peptides HIPs) are antigenic for CD4 T cells and can be detected by mass spectrometry in beta cells. CD4 T cells from the residual pancreatic islets of two organ donors who had T1D also recognize HIPs. Autoreactive T cells targeting hybrid peptides may explain how immune tolerance is broken in T1D.
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