Circulating preproinsulin signal peptide-specific CD8 T cells restricted by the susceptibility molecule HLA-A24 are expanded at onset of type 1 diabetes and kill β-cells

Kronenberg, Deborah, Knight, Robin R., Estorninho, Megan, Ellis, Richard J., Kester, Michael G., de Ru, Arnoud, Eichmann, Martin, Huang, Guo C., Powrie, Jake, Dayan, Colin Mark ORCID: https://orcid.org/0000-0002-6557-3462, Skowera, Ania, van Veelen, Peter A. and Peakman, Mark 2012. Circulating preproinsulin signal peptide-specific CD8 T cells restricted by the susceptibility molecule HLA-A24 are expanded at onset of type 1 diabetes and kill β-cells. Diabetes 61 (7) , pp. 1752-1759. 10.2337/db11-1520

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Abstract

Type 1 diabetes results from T cell-mediated β-cell destruction. The HLA-A*24 class I gene confers significant risk of disease and early onset. We tested the hypothesis that HLA-A24 molecules on islet cells present preproinsulin (PPI) peptide epitopes to CD8 cytotoxic T cells (CTLs). Surrogate β-cell lines secreting proinsulin and expressing HLA-A24 were generated and their peptide ligandome examined by mass spectrometry to discover naturally processed and HLA-A24-presented PPI epitopes. A novel PPI epitope was identified and used to generate HLA-A24 tetramers and examine the frequency of PPI-specific T cells in new-onset HLA-A*24(+) patients and control subjects. We identified a novel naturally processed and HLA-A24-presented PPI signal peptide epitope (PPI(3-11); LWMRLLPLL). HLA-A24 tetramer analysis reveals a significant expansion of PPI(3-11)-specific CD8 T cells in the blood of HLA-A*24(+) recent-onset patients compared with HLA-matched control subjects. Moreover, a patient-derived PPI(3-11)-specific CD8 T-cell clone shows a proinflammatory phenotype and kills surrogate β-cells and human HLA-A*24(+) islet cells in vitro. These results indicate that the type 1 diabetes susceptibility molecule HLA-A24 presents a naturally processed PPI signal peptide epitope. PPI-specific, HLA-A24-restricted CD8 T cells are expanded in patients with recent-onset disease. Human islet cells process and present PPI(3-11), rendering themselves targets for CTL-mediated killing.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > R Medicine (General)
Publisher:	American Diabetes Association
ISSN:	0012-1797
Last Modified:	24 Oct 2022 10:10
URI:	https://orca.cardiff.ac.uk/id/eprint/43324

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