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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Título: | CTLs are targeted to kill β cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope |
Autor/a: | Skowera, Ania Ellis, Richard J. Varela Calviño, Rubén Arif, Sefina Huang, Guo Cai Van-Krinks, Cassie Zaremba, Anna Rackham, Chloe Allen, Jennifer S. Tree, Timothy I. M. Zhao, Min Dayan, Colin M. Sewell, Andrew K. Unger, Wendy W. Drijfhout, Jan W. Ossendorp, Ferry Roep, Bart O. Peakman, Mark |
Centro/Departamento: | Universidade de Santiago de Compostela. Departamento de Bioquímica e Bioloxía Molecular |
Data: | 2008 |
Editor: | American Society for Clinical Investigation |
Cita bibliográfica: | 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 |
Resumo: | 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 |
Descrición: | 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. |
Versión do editor: | https://doi.org/10.1172/JCI35449 |
URI: | http://hdl.handle.net/10347/18527 |
DOI: | 10.1172/JCI35449 |
ISSN: | 0021-9738 |
E-ISSN: | 1558-8238 |
Dereitos: | © 2008 American Society for Clinical Investigation |
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