RT Journal Article
T1 CTLs are targeted to kill β cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope
A1 Skowera, Ania
A1 Ellis, Richard J.
A1 Varela Calviño, Rubén
A1 Arif, Sefina
A1 Huang, Guo Cai
A1 Van-Krinks, Cassie
A1 Zaremba, Anna
A1 Rackham, Chloe
A1 Allen, Jennifer S.
A1 Tree, Timothy I. M.
A1 Zhao, Min
A1 Dayan, Colin M.
A1 Sewell, Andrew K.
A1 Unger, Wendy W.
A1 Drijfhout, Jan W.
A1 Ossendorp, Ferry
A1 Roep, Bart O.
A1 Peakman, Mark
AB 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
PB American Society for Clinical Investigation
SN 0021-9738
YR 2008
FD 2008
LK http://hdl.handle.net/10347/18527
UL http://hdl.handle.net/10347/18527
LA eng
NO Skowera, A., Ellis, R., Varela-Calviño, R., Arif, S., Huang, G., & Van-Krinks, C. et al. (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. doi: 10.1172/jci35449
NO Corrigendum (September 2009). Original citation: J. Clin. Invest.118:3390–3402 (2009). doi:10.1172/JCI35449.Citation for this corrigendum: J. Clin. Invest.119:2843 (2009). doi:10.1172/JCI35449C1.During the preparation of the manuscript, Wendy W. Unger’s name was inadvertently presented incorrectly in the author list. The correct author list appears above.The authors regret the error.
NO This work was supported by grants from Diabetes UK, the Juvenile Diabetes Research Foundation (grant 1-2004-357 to M. Zhao and 7-2005-877 to M. Peakman), the Wellcome Trust (grant 062771 to M. Peakman), and the Spanish Ministry of Education (grant SAF2004-07602 to R. Varela-Calviño)
DS Minerva
RD 30 abr 2026