Epitopes described in "CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope."

Article Authors:Ania Skowera; Richard J Ellis; Ruben Varela-Calviño; Sefina Arif; Guo Cai Huang; Cassie Van-Krinks; Anna Zaremba; Chloe Rackham; Jennifer S Allen; Timothy I M Tree; Min Zhao; Colin M Dayan; Andrew K Sewell; Wendy W Unger; Wendy Unger; Jan W Drijfhout; Ferry Ossendorp; Bart O Roep; Mark Peakman
Article Title:CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope.
Reference Detail
Reference ID:1013774
Abstract:The final pathway of beta cell destruction leading to insulin deficiency, hyperglycemia, and clinical type 1 diabetes is unknown. Here we show that circulating CTLs can kill beta cells via recognition of a glucose-regulated epitope. First, we identified 2 naturally processed epitopes from the human preproinsulin signal peptide by elution from HLA-A2 (specifically, the protein encoded by the A*0201 allele) molecules. Processing of these was unconventional, requiring neither the proteasome nor transporter associated with processing (TAP). However, both epitopes were major targets for circulating effector CD8+ T cells from HLA-A2+ patients with type 1 diabetes. Moreover, cloned preproinsulin signal peptide-specific CD8+ T cells killed human beta cells in vitro. Critically, at high glucose concentration, beta cell presentation of preproinsulin signal epitope increased, as did CTL killing. This study provides direct evidence that autoreactive CTLs are present in the circulation of patients with type 1 diabetes and that they can kill human beta cells. These results also identify a mechanism of self-antigen presentation that is under pathophysiological regulation and could expose insulin-producing beta cells to increasing cytotoxicity at the later stages of the development of clinical diabetes. Our findings suggest that autoreactive CTLs are important targets for immune-based interventions in type 1 diabetes and argue for early, aggressive insulin therapy to preserve remaining beta cells.
Affiliations:Department of Immunobiology, King's College London, London, United Kingdom.
Reference Type:Literature
PubMed ID:18802479
Journal:J Clin Invest
Journal Volume:118
Article Pages:3390-402
Journal ISSN:0021-9738
Article Chemical List:Epitopes, T-Lymphocyte;Insulin;Protein Precursors;Protein Sorting Signals;preproinsulin;Glucose
Article MeSH List:Adolescent; Adult; CD8-Positive T-Lymphocytes(immunology); Diabetes Mellitus, Type 1(immunology; pathology); Epitopes, T-Lymphocyte(drug effects; immunology); Female; Glucose(metabolism; pharmacology); Humans; Insulin(immunology; metabolism); Insulin-Secreting Cells(pathology); K562 Cells; Male; Phenotype; Protein Precursors(immunology; metabolism); Protein Sorting Signals
Article Comments:ErratumIn(J Clin Invest. 2009 Sep;119(9):2844 Unger, Wendy [corrected to Unger, Wendy W] )
Curation Last Updated:2015-09-22 20:01:19