title: CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope.
abstract: The final pathway of beta cell destruction leading to insulin deficiency, hyperglycemia, and clinical type 1 diabetes is unknown. Here we show that circulating CTLs can kill beta 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 beta cells in vitro. Critically, at high glucose concentration, beta 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 beta cells. These results also identify a mechanism of self-antigen presentation that is under pathophysiological regulation and could expose insulin-producing beta 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 beta cells.
authors.affiliation: Department of Immunobiology, King's College London, London, United Kingdom.
authors.forename: Ania
authors.initials: A
authors.lastname: Skowera
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Ellis
authors.forename: Ruben
authors.initials: R
authors.lastname: Varela-Calviño
authors.forename: Sefina
authors.initials: S
authors.lastname: Arif
authors.forename: Guo Cai
authors.initials: GC
authors.lastname: Huang
authors.forename: Cassie
authors.initials: C
authors.lastname: Van-Krinks
authors.forename: Anna
authors.initials: A
authors.lastname: Zaremba
authors.forename: Chloe
authors.initials: C
authors.lastname: Rackham
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Allen
authors.forename: Timothy I M
authors.initials: TI
authors.lastname: Tree
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Colin M
authors.initials: CM
authors.lastname: Dayan
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Unger
authors.forename: Wendy
authors.initials: W
authors.lastname: Unger
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
mesh_terms: D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology*; D018984:Epitopes, T-Lymphocyte / Q000187:drug effects / Q000276:immunology*; D005260:Female; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000276:immunology* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000473:pathology*; D020014:K562 Cells; D008297:Male; D010641:Phenotype; D011498:Protein Precursors / Q000276:immunology* / Q000378:metabolism; D021382:Protein Sorting Signals
chemical_list: D018984:Epitopes, T-Lymphocyte; D007328:Insulin; D011498:Protein Precursors; D021382:Protein Sorting Signals; C013737:preproinsulin; D005947:Glucose