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

Skowera, Ania, Ellis, Richard J., Varela-Calviño, Ruben, Arif, Sefina, Huang, Guo Cai, Van-Krinks, Cassie, Zaremba, Anna, Rackham, Chloe, Allen, Jennifer S., Tree, Timothy I. M., Zhao, Min, Dayan, Colin Mark ORCID: https://orcid.org/0000-0002-6557-3462, Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135, Unger, Wendy, Drijfhout, Jan W., Ossendorp, Ferry, Roep, Bart O. and Peakman, Mark 2008. CTLs are targeted to kill β cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope. Journal of Clinical Investigation 118 (10) , pp. 3390-3402. 10.1172/JCI35449

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology R Medicine > R Medicine (General) R Medicine > RC Internal medicine
Additional Information:	Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0021-9738/ (accessed 24/02/2014)
Publisher:	American Society for Clinical Investigation
ISSN:	0021-9738
Date of First Compliant Deposit:	30 March 2016
Last Modified:	20 May 2023 23:06
URI:	https://orca.cardiff.ac.uk/id/eprint/28637

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