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CTLs are targeted to kill β cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope
Ania Skowera, … , Bart O. Roep, Mark Peakman
Ania Skowera, … , Bart O. Roep, Mark Peakman
Published September 18, 2008
Citation Information: J Clin Invest. 2008;118(10):3390-3402. https://doi.org/10.1172/JCI35449.
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Research Article Article has an altmetric score of 14

CTLs are targeted to kill β cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope

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Abstract

The final pathway of β cell destruction leading to insulin deficiency, hyperglycemia, and clinical type 1 diabetes is unknown. Here we show that circulating CTLs can kill β 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 β cells in vitro. Critically, at high glucose concentration, β 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 β cells. These results also identify a mechanism of self-antigen presentation that is under pathophysiological regulation and could expose insulin-producing β 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 β cells.

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 Unger, Jan W. Drijfhout, Ferry Ossendorp, Bart O. Roep, Mark Peakman

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Figure 3

Circulating effector CD8+ T cells that recognize PPI SP epitopes are present in patients with type 1 diabetes.

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Circulating effector CD8+ T cells that recognize PPI SP epitopes are pre...
IFN-γ ELISPOT PBMC reactivity to PPI15–24, either PPI17–24 or PPI15–24, or both peptides was significantly more frequent in patients with type 1 diabetes and HLA-A*0201 (black bars) than in HLA-matched nondiabetic control subjects (white bars). Responses to PPI17–24 were not significantly different in this series (P = 0.08), but see Supplemental Table 1 showing a similar analysis of an extended, independent series of cases in which the prevalence of responses to PPI17–24 is significantly higher in patients with type 1 diabetes than in control subjects (P = 0.004). In contrast, the prevalence of responses to the mixture of viral peptides was similar in the 2 groups (see also Supplemental Table 1).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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